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UniProtKB/Swiss-Prot entry P05067

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Entry information
Entry name A4_HUMAN
Primary accession number P05067
Secondary accession numbers P09000 P78438 Q13764 Q13778 Q13793 Q16011 Q16014 Q16019 Q16020 Q6GSC0 Q8WZ99 Q9BT38 Q9UC33 Q9UCA9 Q9UCB6 Q9UCC8 Q9UCD1 Q9UQ58
Integrated into Swiss-Prot on August 13, 1987
Sequence was last modified on November 1, 1991 (Sequence version 3)
Annotations were last modified on    June 16, 2009 (Entry version 168)
Name and origin of the protein
Protein name Amyloid beta A4 protein [Precursor]
Synonyms Alzheimer disease amyloid protein
ABPP
APPI
APP
PreA4
Cerebral vascular amyloid peptide
CVAP
Protease nexin-II
PN-II
Contains Soluble APP-alpha
     (S-APP-alpha)
Soluble APP-beta
     (S-APP-beta)
C99
Beta-amyloid protein 42
     (Beta-APP42)
Beta-amyloid protein 40
     (Beta-APP40)
C83
P3(42)
P3(40)
Gamma-secretase C-terminal fragment 59
     (Gamma-CTF(59))
     (Amyloid intracellular domain 59)
     (AICD-59)
     (AID(59))
Gamma-secretase C-terminal fragment 57
     (Gamma-CTF(57))
     (Amyloid intracellular domain 57)
     (AICD-57)
     (AID(57))
Gamma-secretase C-terminal fragment 50
     (Gamma-CTF(50))
     (Amyloid intracellular domain 50)
     (AICD-50)
     (AID(50))
C31
Gene name
Name: APP
Synonyms: A4, AD1
From
Homo sapiens (Human) [TaxID: 9606] 
Taxonomy Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
Protein existence 1: Evidence at protein level;
References
[1]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
TISSUE=Brain;
DOI=10.1038/325733a0; PubMed=2881207 [NCBI, ExPASy, EBI, Israel, Japan]
Kang J., Lemaire H.-G., Unterbeck A., Salbaum J.M., Masters C.L., Grzeschik K.-H., Multhaup G., Beyreuther K., Mueller-Hill B.;
"The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.";
Nature 325:733-736(1987).
[2]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP751).
TISSUE=Brain;
DOI=10.1038/331525a0; PubMed=2893289 [NCBI, ExPASy, EBI, Israel, Japan]
Ponte P., Gonzalez-Dewhitt P., Schilling J., Miller J., Hsu D., Greenberg B., Davis K., Wallace W., Lieberburg I., Fuller F., Cordell B.;
"A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors.";
Nature 331:525-527(1988).
[3]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP695).
DOI=10.1093/nar/17.2.517; PubMed=2783775 [NCBI, ExPASy, EBI, Israel, Japan]
Lemaire H.-G., Salbaum J.M., Multhaup G., Kang J., Bayney R.M., Unterbeck A., Beyreuther K., Mueller-Hill B.;
"The PreA4(695) precursor protein of Alzheimer's disease A4 amyloid is encoded by 16 exons.";
Nucleic Acids Res. 17:517-522(1989).
[4]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP770).
DOI=10.1016/0378-1119(90)90310-N; PubMed=2110105 [NCBI, ExPASy, EBI, Israel, Japan]
Yoshikai S., Sasaki H., Doh-ura K., Furuya H., Sakaki Y.;
"Genomic organization of the human amyloid beta-protein precursor gene.";
Gene 87:257-263(1990).
[5]
 ERRATUM.
DOI=10.1016/0378-1119(91)90093-Q; PubMed=1908403 [NCBI, ExPASy, EBI, Israel, Japan]
Yoshikai S., Sasaki H., Doh-ura K., Furuya H., Sakaki Y.;
Gene 102:291-292(1991).
[6]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM L-APP733).
TISSUE=Leukocyte;
PubMed=1587857 [NCBI, ExPASy, EBI, Israel, Japan]
Koenig G., Moenning U., Czech C., Prior R., Banati R., Schreiter-Gasser U., Bauer J., Masters C.L., Beyreuther K.;
"Identification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells.";
J. Biol. Chem. 267:10804-10809(1992).
[7]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM APP770).
DOI=10.1093/nar/25.9.1802; PubMed=9108164 [NCBI, ExPASy, EBI, Israel, Japan]
Hattori M., Tsukahara F., Furuhata Y., Tanahashi H., Hirose M., Saito M., Tsukuni S., Sakaki Y.;
"A novel method for making nested deletions and its application for sequencing of a 300 kb region of human APP locus.";
Nucleic Acids Res. 25:1802-1808(1997).
[8]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP639), AND TISSUE SPECIFICITY.
TISSUE=Brain;
DOI=10.1046/j.1460-9568.2003.02731.x; PubMed=12859342 [NCBI, ExPASy, EBI, Israel, Japan]
Tang K., Wang C., Shen C., Sheng S., Ravid R., Jing N.;
"Identification of a novel alternative splicing isoform of human amyloid precursor protein gene, APP639.";
Eur. J. Neurosci. 18:102-108(2003).
[9]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-501.
NIEHS SNPs program;
Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
[10]
 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[11]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS APP305 AND APP751).
TISSUE=Eye, and Pancreas;
DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan]
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[12]
 NUCLEOTIDE SEQUENCE [MRNA] OF 1-10.
TISSUE=Liver;
DOI=10.1093/nar/16.19.9351; PubMed=3140222 [NCBI, ExPASy, EBI, Israel, Japan]
Schon E.A., Mita S., Sadlock J., Herbert J.;
"A cDNA specifying the human amyloid beta precursor protein (ABPP) encodes a 95-kDa polypeptide.";
Nucleic Acids Res. 16:9351-9351(1988).
[13]
 ERRATUM, AND SEQUENCE REVISION.
Schon E.A., Mita S., Sadlock J., Herbert J.;
Nucleic Acids Res. 16:11402-11402(1988).
[14]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-75.
DOI=10.1016/0006-291X(89)92437-6; PubMed=2538123 [NCBI, ExPASy, EBI, Israel, Japan]
La Fauci G., Lahiri D.K., Salton S.R., Robakis N.K.;
"Characterization of the 5'-end region and the first two exons of the beta-protein precursor gene.";
Biochem. Biophys. Res. Commun. 159:297-304(1989).
[15]
 PROTEIN SEQUENCE OF 18-50.
TISSUE=Fibroblast;
PubMed=3597385 [NCBI, ExPASy, EBI, Israel, Japan]
van Nostrand W.E., Cunningham D.D.;
"Purification of protease nexin II from human fibroblasts.";
J. Biol. Chem. 262:8508-8514(1987).
[16]
 PROTEIN SEQUENCE OF 18-40.
TISSUE=Platelet;
DOI=10.1038/nbt810; PubMed=12665801 [NCBI, ExPASy, EBI, Israel, Japan]
Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J.;
"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides.";
Nat. Biotechnol. 21:566-569(2003).
[17]
 PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP751).
TISSUE=Brain;
DOI=10.1126/science.2569763; PubMed=2569763 [NCBI, ExPASy, EBI, Israel, Japan]
de Sauvage F., Octave J.-N.;
"A novel mRNA of the A4 amyloid precursor gene coding for a possibly secreted protein.";
Science 245:651-653(1989).
[18]
 PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
TISSUE=Brain;
DOI=10.1073/pnas.84.12.4190; PubMed=3035574 [NCBI, ExPASy, EBI, Israel, Japan]
Robakis N.K., Ramakrishna N., Wolfe G., Wisniewski H.M.;
"Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides.";
Proc. Natl. Acad. Sci. U.S.A. 84:4190-4194(1987).
[19]
 NUCLEOTIDE SEQUENCE [MRNA] OF 286-366.
DOI=10.1038/331528a0; PubMed=2893290 [NCBI, ExPASy, EBI, Israel, Japan]
Tanzi R.E., McClatchey A.I., Lamperti E.D., Villa-Komaroff L., Gusella J.F., Neve R.L.;
"Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease.";
Nature 331:528-530(1988).
[20]
 NUCLEOTIDE SEQUENCE [MRNA] OF 287-367.
DOI=10.1038/331530a0; PubMed=2893291 [NCBI, ExPASy, EBI, Israel, Japan]
Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H.;
"Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity.";
Nature 331:530-532(1988).
[21]
 NUCLEOTIDE SEQUENCE [MRNA] OF 507-770.
TISSUE=Brain cortex;
DOI=10.1073/pnas.85.3.929; PubMed=2893379 [NCBI, ExPASy, EBI, Israel, Japan]
Zain S.B., Salim M., Chou W.G., Sajdel-Sulkowska E.M., Majocha R.E., Marotta C.A.;
"Molecular cloning of amyloid cDNA derived from mRNA of the Alzheimer disease brain: coding and noncoding regions of the fetal precursor mRNA are expressed in the cortex.";
Proc. Natl. Acad. Sci. U.S.A. 85:929-933(1988).
[22]
 PROTEIN SEQUENCE OF 523-555, AND DOMAIN COLLAGEN-BINDING.
DOI=10.1074/jbc.271.3.1613; PubMed=8576160 [NCBI, ExPASy, EBI, Israel, Japan]
Beher D., Hesse L., Masters C.L., Multhaup G.;
"Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I.";
J. Biol. Chem. 271:1613-1620(1996).
[23]
 NUCLEOTIDE SEQUENCE [MRNA] OF 655-737, AND VARIANTS AD1 GLY-717; ILE-717 AND PHE-717.
DOI=10.1006/bbrc.1993.1386; PubMed=8476439 [NCBI, ExPASy, EBI, Israel, Japan]
Denman R.B., Rosenzcwaig R., Miller D.L.;
"A system for studying the effect(s) of familial Alzheimer disease mutations on the processing of the beta-amyloid peptide precursor.";
Biochem. Biophys. Res. Commun. 192:96-103(1993).
[24]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
DOI=10.1016/0006-291X(89)91112-1; PubMed=2675837 [NCBI, ExPASy, EBI, Israel, Japan]
Johnstone E.M., Chaney M.O., Moore R.E., Ward K.E., Norris F.H., Little S.P.;
"Alzheimer's disease amyloid peptide is encoded by two exons and shows similarity to soybean trypsin inhibitor.";
Biochem. Biophys. Res. Commun. 163:1248-1255(1989).
[25]
 NUCLEOTIDE SEQUENCE [MRNA] OF 672-723, AND VARIANT AD1 ASN-678.
DOI=10.1136/jnnp.2003.010611; PubMed=15201367 [NCBI, ExPASy, EBI, Israel, Japan]
Wakutani Y., Watanabe K., Adachi Y., Wada-Isoe K., Urakami K., Ninomiya H., Saido T.C., Hashimoto T., Iwatsubo T., Nakashima K.;
"Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease.";
J. Neurol. Neurosurg. Psych. 75:1039-1042(2004).
[26]
 PROTEIN SEQUENCE OF 672-713.
TISSUE=Blood vessel;
DOI=10.1073/pnas.90.22.10836; PubMed=8248178 [NCBI, ExPASy, EBI, Israel, Japan]
Roher A.E., Lowenson J.D., Clarke S., Woods A.S., Cotter R.J., Gowing E., Ball M.J.;
"Beta-amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease.";
Proc. Natl. Acad. Sci. U.S.A. 90:10836-10840(1993).
[27]
 PROTEIN SEQUENCE OF 672-704, AND TISSUE SPECIFICITY.
DOI=10.1038/359325a0; PubMed=1406936 [NCBI, ExPASy, EBI, Israel, Japan]
Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D., Sinha S., Schlossmacher M., Whaley J., Swindlehurst C.;
"Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids.";
Nature 359:325-327(1992).
[28]
 PROTEIN SEQUENCE OF 672-701 AND 707-713.
DOI=10.1002/ana.410350223; PubMed=8109908 [NCBI, ExPASy, EBI, Israel, Japan]
Wisniewski T., Lalowski M., Levy E., Marques M.R.F., Frangione B.;
"The amino acid sequence of neuritic plaque amyloid from a familial Alzheimer's disease patient.";
Ann. Neurol. 35:245-246(1994).
[29]
 PROTEIN SEQUENCE OF 672-701.
TISSUE=Cerebrospinal fluid;
DOI=10.1111/j.1471-4159.1993.tb09841.x; PubMed=8229004 [NCBI, ExPASy, EBI, Israel, Japan]
Vigo-Pelfrey C., Lee D., Keim P., Lieberburg I., Schenk D.B.;
"Characterization of beta-amyloid peptide from human cerebrospinal fluid.";
J. Neurochem. 61:1965-1968(1993).
[30]
 PROTEIN SEQUENCE OF 672-681.
TISSUE=Brain cortex;
DOI=10.1111/j.1471-4159.1987.tb01005.x; PubMed=3312495 [NCBI, ExPASy, EBI, Israel, Japan]
Pardridge W.M., Vinters H.V., Yang J., Eisenberg J., Choi T.B., Tourtellotte W.W., Huebner V., Shively J.E.;
"Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-dalton peptide isolated from cortical microvessels.";
J. Neurochem. 49:1394-1401(1987).
[31]
 NUCLEOTIDE SEQUENCE [MRNA] OF 674-770.
TISSUE=Brain;
DOI=10.1126/science.3810169; PubMed=3810169 [NCBI, ExPASy, EBI, Israel, Japan]
Goldgaber D., Lerman M.I., McBride O.W., Saffiotti U., Gajdusek D.C.;
"Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease.";
Science 235:877-880(1987).
[32]
 NUCLEOTIDE SEQUENCE [MRNA] OF 674-703.
TISSUE=Fetal brain;
DOI=10.1126/science.2949367; PubMed=2949367 [NCBI, ExPASy, EBI, Israel, Japan]
Tanzi R.E., Gusella J.F., Watkins P.C., Bruns G.A., St George-Hyslop P.H., Van Keuren M.L., Patterson D., Pagan S., Kurnit D.M., Neve R.L.;
"Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus.";
Science 235:880-884(1987).
[33]
 CHARACTERIZATION OF L-APP733, AND MUTAGENESIS OF SER-656.
DOI=10.1074/jbc.270.18.10388; PubMed=7737970 [NCBI, ExPASy, EBI, Israel, Japan]
Pangalos M.N., Efthimiopoulos S., Shioi J., Robakis N.K.;
"The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene.";
J. Biol. Chem. 270:10388-10391(1995).
[34]
 FUNCTION OF BETA-AMYLOID PEPTIDE AS LIPID PEROXIDATION INHIBITOR, AND MUTAGENESIS OF MET-706.
DOI=10.1006/bbrc.1997.6547; PubMed=9168929 [NCBI, ExPASy, EBI, Israel, Japan]
Walter M.F., Mason P.E., Mason R.P.;
"Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions.";
Biochem. Biophys. Res. Commun. 233:760-764(1997).
[35]
 REVIEW ON FUNCTION OF BETA-AMYLOID AS ANTIOXIDANT.
DOI=10.1023/A:1012629603390; PubMed=11775062 [NCBI, ExPASy, EBI, Israel, Japan]
Kontush A.;
"Alzheimer's amyloid-beta as a preventive antioxidant for brain lipoproteins.";
Cell. Mol. Neurobiol. 21:299-315(2001).
[36]
 IDENTITY OF APP WITH NEXIN-II.
DOI=10.1038/341144a0; PubMed=2506449 [NCBI, ExPASy, EBI, Israel, Japan]
Oltersdorf T., Fritz L.C., Schenk D.B., Lieberburg I., Johnson-Wood K.L., Beattie E.C., Ward P.J., Blacher R.W., Dovey H.F., Sinha S.;
"The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II.";
Nature 341:144-147(1989).
[37]
 PROTEASE-SPECIFICITY OF INHIBITOR DOMAIN.
DOI=10.1016/0006-291X(90)92084-D; PubMed=1969731 [NCBI, ExPASy, EBI, Israel, Japan]
Kido H., Fukutomi A., Schilling J., Wang Y., Cordell B., Katunuma N.;
"Protease-specificity of Kunitz inhibitor domain of Alzheimer's disease amyloid protein precursor.";
Biochem. Biophys. Res. Commun. 167:716-721(1990).
[38]
 EXTRACELLULAR ZINC-BINDING DOMAIN.
PubMed=8344894 [NCBI, ExPASy, EBI, Israel, Japan]
Bush A.I., Multhaup G., Moir R.D., Williamson T.G., Small D.H., Rumble B., Pollwein P., Beyreuther K., Masters C.L.;
"A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease.";
J. Biol. Chem. 268:16109-16112(1993).
[39]
 COMPLEX WITH G(O).
DOI=10.1038/362075a0; PubMed=8446172 [NCBI, ExPASy, EBI, Israel, Japan]
Nishimoto I., Okamoto T., Matsuura Y., Takahashi S., Okamoto T., Murayama Y., Ogata E.;
"Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o).";
Nature 362:75-79(1993).
[40]
 EXTRACELLULAR COPPER-BINDING DOMAIN, AND MUTAGENESIS OF HIS-137; MET-141; CYS-144; HIS-147 AND HIS-151.
DOI=10.1016/0014-5793(94)00658-X; PubMed=7913895 [NCBI, ExPASy, EBI, Israel, Japan]
Hesse L., Beher D., Masters C.L., Multhaup G.;
"The beta A4 amyloid precursor protein binding to copper.";
FEBS Lett. 349:109-116(1994).
[41]
 N-TERMINAL HEPARIN-BINDING DOMAIN, AND MUTAGENESIS OF 99-LYS--ARG-102.
PubMed=8158260 [NCBI, ExPASy, EBI, Israel, Japan]
Small D.H., Nurcombe V., Reed G., Clarris H., Moir R., Beyreuther K., Masters C.L.;
"A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth.";
J. Neurosci. 14:2117-2127(1994).
[42]
 MUTAGENESIS OF VAL-717.
DOI=10.1006/bbrc.1996.1577; PubMed=8886002 [NCBI, ExPASy, EBI, Israel, Japan]
Maruyama K., Tomita T., Shinozaki K., Kume H., Asada H., Saido T.C., Ishiura S., Iwatsubo T., Obata K.;
"Familial Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of A beta 42(43).";
Biochem. Biophys. Res. Commun. 227:730-735(1996).
[43]
 INTERACTION WITH APP-BP1.
DOI=10.1074/jbc.271.19.11339; PubMed=8626687 [NCBI, ExPASy, EBI, Israel, Japan]
Chow N., Korenberg J.R., Chen X.-N., Neve R.L.;
"APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein.";
J. Biol. Chem. 271:11339-11346(1996).
[44]
 INTERACTION WITH APBA1 AND APBB1, AND MUTAGENESIS OF TYR-728; TYR-757; ASN-759 AND TYR-762.
PubMed=8887653 [NCBI, ExPASy, EBI, Israel, Japan]
Borg J.-P., Ooi J., Levy E., Margolis B.;
"The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.";
Mol. Cell. Biol. 16:6229-6241(1996).
[45]
 INTERACTION WITH APBB2.
DOI=10.1073/pnas.93.20.10832; PubMed=8855266 [NCBI, ExPASy, EBI, Israel, Japan]
Guenette S.Y., Chen J., Jondro P.D., Tanzi R.E.;
"Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein.";
Proc. Natl. Acad. Sci. U.S.A. 93:10832-10837(1996).
[46]
 HEPARIN-BINDING DOMAINS.
DOI=10.1016/S0014-5793(97)01146-0; PubMed=9357988 [NCBI, ExPASy, EBI, Israel, Japan]
Mok S.S., Sberna G., Heffernan D., Cappai R., Galatis D., Clarris H.J., Sawyer W.H., Beyreuther K., Masters C.L., Small D.H.;
"Expression and analysis of heparin-binding regions of the amyloid precursor protein of Alzheimer's disease.";
FEBS Lett. 415:303-307(1997).
[47]
 INTERACTION OF BETA-AMYLOID PEPTIDE WITH HADH2.
TISSUE=Brain;
DOI=10.1038/39522; PubMed=9338779 [NCBI, ExPASy, EBI, Israel, Japan]
Yan S.D., Fu J., Soto C., Chen X., Zhu H., Al-Mohanna F., Collinson K., Zhu A., Stern E., Saido T., Tohyama M., Ogawa S., Roher A., Stern D.;
"An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease.";
Nature 389:689-695(1997).
[48]
 INTERACTION WITH APPBP2, AND MUTAGENESIS OF TYR-728.
DOI=10.1073/pnas.95.25.14745; PubMed=9843960 [NCBI, ExPASy, EBI, Israel, Japan]
Zheng P., Eastman J., Vande Pol S., Pimplikar S.W.;
"PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein.";
Proc. Natl. Acad. Sci. U.S.A. 95:14745-14750(1998).
[49]
 BETA-AMYLOID ZINC-BINDING, AND MUTAGENESIS OF ARG-676; TYR-681 AND HIS-684.
DOI=10.1021/bi990205o; PubMed=10413512 [NCBI, ExPASy, EBI, Israel, Japan]
Liu S.T., Howlett G., Barrow C.J.;
"Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease.";
Biochemistry 38:9373-9378(1999).
[50]
 IMPORTANCE OF MET-706 IN FREE RADICAL OXIDATIVE STRESS, AND MUTAGENESIS OF MET-706.
DOI=10.1016/S0361-9230(99)00093-3; PubMed=10535332 [NCBI, ExPASy, EBI, Israel, Japan]
Varadarajan S., Yatin S., Kanski J., Jahanshahi F., Butterfield D.A.;
"Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress.";
Brain Res. Bull. 50:133-141(1999).
[51]
 INTERACTION WITH APBA2.
DOI=10.1074/jbc.274.4.2243; PubMed=9890987 [NCBI, ExPASy, EBI, Israel, Japan]
Tomita S., Ozaki T., Taru H., Oguchi S., Takeda S., Yagi Y., Sakiyama S., Kirino Y., Suzuki T.;
"Interaction of a neuron-specific protein containing PDZ domains with Alzheimer's amyloid precursor protein.";
J. Biol. Chem. 274:2243-2254(1999).
[52]
 ENDOCYTOSIS SIGNAL, AND MUTAGENESIS OF TYR-728; GLY-756; TYR-757; ASN-759; PRO-760 AND TYR-762.
DOI=10.1074/jbc.274.27.18851; PubMed=10383380 [NCBI, ExPASy, EBI, Israel, Japan]
Perez R.G., Soriano S., Hayes J.D., Ostaszewski B., Xia W., Selkoe D.J., Chen X., Stokin G.B., Koo E.H.;
"Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42.";
J. Biol. Chem. 274:18851-18856(1999).
[53]
 IMPORTANCE OF CYS-144 IN COPPER REDUCTION, AND MUTAGENESIS OF CYS-144 AND 147-HIS--HIS-149.
DOI=10.1046/j.1471-4159.1999.0731288.x; PubMed=10461923 [NCBI, ExPASy, EBI, Israel, Japan]
Ruiz F.H., Gonzalez M., Bodini M., Opazo C., Inestrosa N.C.;
"Cysteine 144 is a key residue in the copper reduction by the beta-amyloid precursor protein.";
J. Neurochem. 73:1288-1292(1999).
[54]
 INTERACTION OF BETA-AMYLOID WITH APOE.
DOI=10.1042/0264-6021:3480359; PubMed=10816430 [NCBI, ExPASy, EBI, Israel, Japan]
Tokuda T., Calero M., Matsubara E., Vidal R., Kumar A., Permanne B., Zlokovic B., Smith J.D., Ladu M.J., Rostagno A., Frangione B., Ghiso J.;
"Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides.";
Biochem. J. 348:359-365(2000).
[55]
 INTERACTION OF BETA-APP42 WITH CHRNA7.
DOI=10.1074/jbc.275.8.5626; PubMed=10681545 [NCBI, ExPASy, EBI, Israel, Japan]
Wang H.-Y., Lee D.H.S., D'Andrea M.R., Peterson P.A., Shank R.P., Reitz A.B.;
"Beta-amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology.";
J. Biol. Chem. 275:5626-5632(2000).
[56]
 IDENTIFICATION OF GAMMA-CTFS BY MASS SPECTROMETRY, AND MUTAGENESIS OF ASP-739.
PubMed=12214090 [NCBI, ExPASy, EBI, Israel, Japan]
Passer B., Pellegrini L., Russo C., Siegel R.M., Lenardo M.J., Schettini G., Bachmann M., Tabaton M., D'Adamio L.;
"Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of Alzheimer's amyloid beta protein precursor.";
J. Alzheimers Dis. 2:289-301(2000).
[57]
 INTERACTION WITH FPRL1.
DOI=10.1096/fj.01-0251com; PubMed=11689470 [NCBI, ExPASy, EBI, Israel, Japan]
Yazawa H., Yu Z.-X., Takeda K., Le Y., Gong W., Ferrans V.J., Oppenheim J.J., Li C.C.H., Wang J.M.;
"Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages.";
FASEB J. 15:2454-2462(2001).
[58]
 INTERACTION WITH BBP.
DOI=10.1074/jbc.M011161200; PubMed=11278849 [NCBI, ExPASy, EBI, Israel, Japan]
Kajkowski E.M., Lo C.F., Ning X., Walker S., Sofia H.J., Wang W., Edris W., Chanda P., Wagner E., Vile S., Ryan K., McHendry-Rinde B., Smith S.C., Wood A., Rhodes K.J., Kennedy J.D., Bard J., Jacobsen J.S., Ozenberger B.A.;
"Beta-amyloid peptide-induced apoptosis regulated by a novel protein containing a G protein activation module.";
J. Biol. Chem. 276:18748-18756(2001).
[59]
 BETA-AMYLOID COPPER AND ZINC-BINDING.
DOI=10.1074/jbc.M100175200; PubMed=11274207 [NCBI, ExPASy, EBI, Israel, Japan]
Curtain C.C., Ali F., Volitakis I., Cherny R.A., Norton R.S., Beyreuther K., Barrow C.J., Masters C.L., Bush A.I., Barnham K.J.;
"Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered structure containing superoxide dismutase-like subunits.";
J. Biol. Chem. 276:20466-20473(2001).
[60]
 SUBUNIT.
DOI=10.1074/jbc.M105410200; PubMed=11438549 [NCBI, ExPASy, EBI, Israel, Japan]
Scheuermann S., Hambsch B., Hesse L., Stumm J., Schmidt C., Beher D., Bayer T.A., Beyreuther K., Multhaup G.;
"Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer's disease.";
J. Biol. Chem. 276:33923-33929(2001).
[61]
 INTERACTION WITH APBB1, FUNCTION, AND SUBCELLULAR LOCATION.
DOI=10.1074/jbc.C100447200; PubMed=11544248 [NCBI, ExPASy, EBI, Israel, Japan]
Kimberly W.T., Zheng J.B., Guenette S.Y., Selkoe D.J.;
"The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner.";
J. Biol. Chem. 276:40288-40292(2001).
[62]
 INTERACTION WITH FBLN1.
DOI=10.1046/j.1471-4159.2001.00144.x; PubMed=11238726 [NCBI, ExPASy, EBI, Israel, Japan]
Ohsawa I., Takamura C., Kohsaka S.;
"Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function.";
J. Neurochem. 76:1411-1420(2001).
[63]
 INTERACTION WITH MAPT, AND FUNCTION.
DOI=10.1016/S0014-5793(02)02376-1; PubMed=11943163 [NCBI, ExPASy, EBI, Israel, Japan]
Rank K.B., Pauley A.M., Bhattacharya K., Wang Z., Evans D.B., Fleck T.J., Johnston J.A., Sharma S.K.;
"Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II.";
FEBS Lett. 514:263-268(2002).
[64]
 INTERACTION WITH MAPK8IP1, AND MUTAGENESIS OF TYR-757.
DOI=10.1074/jbc.M108357200; PubMed=11724784 [NCBI, ExPASy, EBI, Israel, Japan]
Scheinfeld M.H., Roncarati R., Vito P., Lopez P.A., Abdallah M., D'Adamio L.;
"Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP).";
J. Biol. Chem. 277:3767-3775(2002).
[65]
 COPPER-MEDIATED LIPID PEROXIDATION, AND MUTAGENESIS OF HIS-147 AND HIS-151.
PubMed=11784781 [NCBI, ExPASy, EBI, Israel, Japan]
White A.R., Multhaup G., Galatis D., McKinstry W.J., Parker M.W., Pipkorn R., Beyreuther K., Masters C.L., Cappai R.;
"Contrasting species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein.";
J. Neurosci. 22:365-376(2002).
[66]
 REVIEW ON ZINC-BINDING.
DOI=10.1073/pnas.122249699; PubMed=12032279 [NCBI, ExPASy, EBI, Israel, Japan]
Bush A.I., Tanzi R.E.;
"The galvanization of beta-amyloid in Alzheimer's disease.";
Proc. Natl. Acad. Sci. U.S.A. 99:7317-7319(2002).
[67]
 INTERACTION WITH ANKS1B.
DOI=10.1074/jbc.M405329200; PubMed=15347684 [NCBI, ExPASy, EBI, Israel, Japan]
Ghersi E., Noviello C., D'Adamio L.;
"Amyloid-beta protein precursor (AbetaPP) intracellular domain-associated protein-1 proteins bind to AbetaPP and modulate its processing in an isoform-specific manner.";
J. Biol. Chem. 279:49105-49112(2004).
[68]
 PHOSPHORYLATION AT THR-743.
PubMed=8131745 [NCBI, ExPASy, EBI, Israel, Japan]
Suzuki T., Oishi M., Marshak D.R., Czernik A.J., Nairn A.C., Greengard P.;
"Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein.";
EMBO J. 13:1114-1122(1994).
[69]
 PHOSPHORYLATION BY CASEIN KINASES, AND MUTAGENESIS OF SER-198 AND SER-206.
DOI=10.1074/jbc.272.3.1896; PubMed=8999878 [NCBI, ExPASy, EBI, Israel, Japan]
Walter J., Capell A., Hung A.Y., Langen H., Schnoelzer M., Thinakaran G., Sisodia S.S., Selkoe D.J., Haass C.;
"Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations.";
J. Biol. Chem. 272:1896-1903(1997).
[70]
 COPPER-BINDING, AND DISULFIDE BOND FORMATION.
DOI=10.1021/bi980022m; PubMed=9585534 [NCBI, ExPASy, EBI, Israel, Japan]
Multhaup G., Ruppert T., Schlicksupp A., Hesse L., Bill E., Pipkorn R., Masters C.L., Beyreuther K.;
"Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide.";
Biochemistry 37:7224-7230(1998).
[71]
 CLEAVAGE BY CASPASES, AND MUTAGENESIS OF ASP-739.
DOI=10.1016/S0092-8674(00)80748-5; PubMed=10319819 [NCBI, ExPASy, EBI, Israel, Japan]
Gervais F.G., Xu D., Robertson G.S., Vaillancourt J.P., Zhu Y., Huang J., LeBlanc A., Smith D., Rigby M., Shearman M.S., Clarke E.E., Zheng H., van der Ploeg L.H.T., Ruffolo S.C., Thornberry N.A., Xanthoudakis S., Zamboni R.J., Roy S., Nicholson D.W.;
"Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.";
Cell 97:395-406(1999).
[72]
 PHOSPHORYLATION, AND MUTAGENESIS OF THR-743.
PubMed=10341243 [NCBI, ExPASy, EBI, Israel, Japan]
Ando K., Oishi M., Takeda S., Iijima K., Isohara T., Nairn A.C., Kirino Y., Greengard P., Suzuki T.;
"Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation.";
J. Neurosci. 19:4421-4427(1999).
[73]
 CHARACTERIZATION OF CASEIN KINASE PHOSPHORYLATION, AND MUTAGENESIS OF SER-198 AND SER-206.
DOI=10.1074/jbc.M002850200; PubMed=10806211 [NCBI, ExPASy, EBI, Israel, Japan]
Walter J., Schindzielorz A., Hartung B., Haass C.;
"Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2.";
J. Biol. Chem. 275:23523-23529(2000).
[74]
 CLEAVAGE BY CASPASES, AND MUTAGENESIS OF ASP-739.
DOI=10.1038/74656; PubMed=10742146 [NCBI, ExPASy, EBI, Israel, Japan]
Lu D.C., Rabizadeh S., Chandra S., Shayya R.F., Ellerby L.M., Ye X., Salvesen G.S., Koo E.H., Bredesen D.E.;
"A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor.";
Nat. Med. 6:397-404(2000).
[75]
 PHOSPHORYLATION, COMPLEX WITH APBB1, AND MUTAGENESIS OF THR-743.
DOI=10.1074/jbc.M104059200; PubMed=11517218 [NCBI, ExPASy, EBI, Israel, Japan]
Ando K., Iijima K., Elliott J.I., Kirino Y., Suzuki T.;
"Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.";
J. Biol. Chem. 276:40353-40361(2001).
[76]
 PHOSPHORYLATION BY MAPK10, AND MUTAGENESIS OF THR-743.
DOI=10.1046/j.1471-4159.2001.00102.x; PubMed=11146006 [NCBI, ExPASy, EBI, Israel, Japan]
Standen C.L., Brownlees J., Grierson A.J., Kesavapany S., Lau K.-F., McLoughlin D.M., Miller C.C.J.;
"Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer's disease amyloid precursor protein by stress-activated protein kinase 1b (Jun N-terminal kinase-3).";
J. Neurochem. 76:316-320(2001).
[77]
 CLEAVAGE AT LEU-720.
DOI=10.1021/bi015794o; PubMed=11851430 [NCBI, ExPASy, EBI, Israel, Japan]
Weidemann A., Eggert S., Reinhard F.B.M., Vogel M., Paliga K., Baier G., Masters C.L., Beyreuther K., Evin G.;
"A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing.";
Biochemistry 41:2825-2835(2002).
[78]
 PHOSPHORYLATION AT TYROSINE RESIDUES, INTERACTION WITH SHC1, AND MUTAGENESIS OF THR-743 AND TYR-757.
DOI=10.1074/jbc.M110286200; PubMed=11877420 [NCBI, ExPASy, EBI, Israel, Japan]
Tarr P.E., Roncarati R., Pelicci G., Pelicci P.G., D'Adamio L.;
"Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc.";
J. Biol. Chem. 277:16798-16804(2002).
[79]
 GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-542, AND MASS SPECTROMETRY.
TISSUE=Plasma;
DOI=10.1021/pr0502065; PubMed=16335952 [NCBI, ExPASy, EBI, Israel, Japan]
Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D.;
"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.";
J. Proteome Res. 4:2070-2080(2005).
[80]
 SIGNAL SEQUENCE CLEAVAGE SITE, AND TOPOLOGY.
PubMed=2900137 [NCBI, ExPASy, EBI, Israel, Japan]
Dyrks T., Weidemann A., Multhaup G., Salbaum J.M., Lemaire H.-G., Kang J., Mueller-Hill B., Masters C.L., Beyreuther K.;
"Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease.";
EMBO J. 7:949-957(1988).
[81]
 REVIEW.
DOI=10.1146/annurev.cellbio.18.020402.142302; PubMed=12142279 [NCBI, ExPASy, EBI, Israel, Japan]
Annaert W., De Strooper B.;
"A cell biological perspective on Alzheimer's disease.";
Annu. Rev. Cell Dev. Biol. 18:25-51(2002).
[82]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-757 AND TYR-762, AND MASS SPECTROMETRY.
DOI=10.1016/j.cell.2007.11.025; PubMed=18083107 [NCBI, ExPASy, EBI, Israel, Japan]
Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.;
"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.";
Cell 131:1190-1203(2007).
[83]
 INTERACTION WITH APBB1.
DOI=10.1074/jbc.M801827200; PubMed=18468999 [NCBI, ExPASy, EBI, Israel, Japan]
Nakaya T., Kawai T., Suzuki T.;
"Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells.";
J. Biol. Chem. 283:19119-19131(2008).
[84]
 X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 287-344.
DOI=10.1021/bi00495a002; PubMed=2125487 [NCBI, ExPASy, EBI, Israel, Japan]
Hynes T.R., Randal M., Kennedy L.A., Eigenbrot C., Kossiakof A.A.;
"X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor.";
Biochemistry 29:10018-10022(1990).
[85]
 STRUCTURE BY NMR OF 289-344.
DOI=10.1021/bi00107a015; PubMed=1718421 [NCBI, ExPASy, EBI, Israel, Japan]
Heald S.L., Tilton R.F. Jr., Hammond L.S., Lee A., Bayney R.M., Kamarck M.E., Ramabhadran T.V., Dreyer R.N., Davis G., Unterbeck A., Tamburini P.P.;
"Sequential NMR resonance assignment and structure determination of the Kunitz-type inhibitor domain of the Alzheimer's beta-amyloid precursor protein.";
Biochemistry 30:10467-10478(1991).
[86]
 STRUCTURE BY NMR OF 672-699.
DOI=10.1021/bi00191a006; PubMed=7516706 [NCBI, ExPASy, EBI, Israel, Japan]
Talafous J., Marcinowski K.J., Klopman G., Zagorski M.G.;
"Solution structure of residues 1-28 of the amyloid beta-peptide.";
Biochemistry 33:7788-7796(1994).
[87]
 STRUCTURE BY NMR OF 672-711.
DOI=10.1111/j.1432-1033.1995.293_1.x; PubMed=7588758 [NCBI, ExPASy, EBI, Israel, Japan]
Sticht H., Bayer P., Willbold D., Dames S., Hilbich C., Beyreuther K., Frank R.W., Rosch P.;
"Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease.";
Eur. J. Biochem. 233:293-298(1995).
[88]
 STRUCTURE BY NMR OF 696-706.
DOI=10.1021/bi961598j; PubMed=8973180 [NCBI, ExPASy, EBI, Israel, Japan]
Kohno T., Kobayashi K., Maeda T., Sato K., Takashima A.;
"Three-dimensional structures of the amyloid beta peptide (25-35) in membrane-mimicking environment.";
Biochemistry 35:16094-16104(1996).
[89]
 X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF KUNITZ DOMAIN IN COMPLEX WITH CHYMOTRYPSIN; TRYPSIN AND BASIC PANCREATIC TRYPSIN INHIBITOR.
PubMed=9300481 [NCBI, ExPASy, EBI, Israel, Japan]
Scheidig A.J., Hynes T.R., Pelletier L.A., Wells J.A., Kossiakoff A.A.;
"Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimer's amyloid beta-protein precursor (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with altered specificities.";
Protein Sci. 6:1806-1824(1997).
[90]
 STRUCTURE BY NMR OF 672-711.
DOI=10.1021/bi972979f; PubMed=9693002 [NCBI, ExPASy, EBI, Israel, Japan]
Coles M., Bicknell W., Watson A.A., Fairlie D.P., Craik D.J.;
"Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is?";
Biochemistry 37:11064-11077(1998).
[91]
 X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 28-123.
DOI=10.1038/7562; PubMed=10201399 [NCBI, ExPASy, EBI, Israel, Japan]
Rossjohn J., Cappai R., Feil S.C., Henry A., McKinstry W.J., Galatis D., Hesse L., Multhaup G., Beyreuther K., Masters C.L., Parker M.W.;
"Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein.";
Nat. Struct. Biol. 6:327-331(1999).
[92]
 STRUCTURE OF AMYLCAD VARIANTS.
DOI=10.1074/jbc.M003154200; PubMed=10821838 [NCBI, ExPASy, EBI, Israel, Japan]
Miravalle L., Tokuda T., Chiarle R., Giaccone G., Bugiani O., Tagliavini F., Frangione B., Ghiso J.;
"Substitutions at codon 22 of Alzheimer's Abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells.";
J. Biol. Chem. 275:27110-27116(2000).
[93]
 STRUCTURE BY NMR OF 681-706.
DOI=10.1006/jsbi.2000.4288; PubMed=10940221 [NCBI, ExPASy, EBI, Israel, Japan]
Zhang S., Iwata K., Lachenmann M.J., Peng J.W., Li S., Stimson E.R., Lu Y., Felix A.M., Maggio J.E., Lee J.P.;
"The Alzheimer's peptide a beta adopts a collapsed coil structure in water.";
J. Struct. Biol. 130:130-141(2000).
[94]
 STRUCTURE BY NMR OF 672-699.
DOI=10.1006/jsbi.2000.4267; PubMed=10940222 [NCBI, ExPASy, EBI, Israel, Japan]
Poulsen S.-A., Watson A.A., Craik D.J.;
"Solution structures in aqueous SDS micelles of two amyloid beta peptides of Abeta(1-28) mutated at the alpha-secretase cleavage site.";
J. Struct. Biol. 130:142-152(2000).
[95]
 X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 346-551, PARTIAL PROTEIN SEQUENCE, MASS SPECTROMETRY, AND MUTAGENESIS OF ARG-499 AND LYS-503.
DOI=10.1016/j.molcel.2004.06.037; PubMed=15304215 [NCBI, ExPASy, EBI, Israel, Japan]
Wang Y., Ha Y.;
"The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain.";
Mol. Cell 15:343-353(2004).
[96]
 REVIEW ON VARIANTS.
DOI=10.1038/ng0792-233; PubMed=1363811 [NCBI, ExPASy, EBI, Israel, Japan]
Hardy J.;
"Framing beta-amyloid.";
Nat. Genet. 1:233-234(1992).
[97]
 VARIANT AMYLCAD GLN-693.
DOI=10.1126/science.2111584; PubMed=2111584 [NCBI, ExPASy, EBI, Israel, Japan]
Levy E., Carman M.D., Fernandez-Madrid I.J., Power M.D., Lieberburg I., van Duinen S.G., Bots G.T.A.M., Luyendijk W., Frangione B.;
"Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.";
Science 248:1124-1126(1990).
[98]
 VARIANT AD1 ILE-717.
DOI=10.1038/349704a0; PubMed=1671712 [NCBI, ExPASy, EBI, Israel, Japan]
Goate A., Chartier-Harlin M.-C., Mullan M., Brown J., Crawford F., Fidani L., Giuffra L., Haynes A., Irving N., James L., Mant R., Newton P., Rooke K., Roques P., Talbot C., Pericak-Vance M., Roses A.D., Williamson R., Rossor M., Owen M., Hardy J.;
"Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.";
Nature 349:704-706(1991).
[99]
 VARIANT AD1 ILE-717.
DOI=10.1016/0006-291X(91)91011-Z; PubMed=1908231 [NCBI, ExPASy, EBI, Israel, Japan]
Yoshioka K., Miki T., Katsuya T., Ogihara T., Sakaki Y.;
"The 717Val-->Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups.";
Biochem. Biophys. Res. Commun. 178:1141-1146(1991).
[100]
 VARIANT AD1 ILE-717.
DOI=10.1016/0140-6736(91)91612-X; PubMed=1678058 [NCBI, ExPASy, EBI, Israel, Japan]
Naruse S., Igarashi S., Kobayashi H., Aoki K., Inuzuka T., Kaneko K., Shimizu T., Iihara K., Kojima T., Miyatake T., Tsuji S.;
"Mis-sense mutation Val->Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease.";
Lancet 337:978-979(1991).
[101]
 VARIANT AD1 GLY-717.
DOI=10.1038/353844a0; PubMed=1944558 [NCBI, ExPASy, EBI, Israel, Japan]
Chartier-Harlin M.-C., Crawford F., Houlden H., Warren A., Hughes D., Fidani L., Goate A., Rossor M., Roques P., Hardy J., Mullan M.;
"Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.";
Nature 353:844-846(1991).
[102]
 VARIANT AD1 PHE-717.
DOI=10.1126/science.1925564; PubMed=1925564 [NCBI, ExPASy, EBI, Israel, Japan]
Murrell J.R., Farlow M., Ghetti B., Benson M.D.;
"A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.";
Science 254:97-99(1991).
[103]
 VARIANT AD1 GLY-693.
PubMed=1415269 [NCBI, ExPASy, EBI, Israel, Japan]
Kamino K., Orr H.T., Payami H., Wijsman E.M., Alonso M.E., Pulst S.M., Anderson L., O'Dahl S., Nemens E., White J.A., Sadovnick A.D., Ball M.J., Kaye J., Warren A., McInnis M.G., Antonarakis S.E., Korenberg J.R., Sharma V., Kukull W., Larson E., Heston L.L., Martin G.M., Bird T.D., Schellenberg G.D.;
"Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region.";
Am. J. Hum. Genet. 51:998-1014(1992).
[104]
 VARIANT AD1 GLY-692.
DOI=10.1038/ng0692-218; PubMed=1303239 [NCBI, ExPASy, EBI, Israel, Japan]
Hendriks L., van Duijn C.M., Cras P., Cruts M., Van Hul W., van Harskamp F., Warren A., McInnis M.G., Antonarakis S.E., Martin J.J., Hofman A., Van Broeckhoven C.;
"Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene.";
Nat. Genet. 1:218-221(1992).
[105]
 VARIANT AD1 670-ASN-LEU-671.
DOI=10.1038/ng0892-345; PubMed=1302033 [NCBI, ExPASy, EBI, Israel, Japan]
Mullan M., Crawford F., Axelman K., Houlden H., Lilius L., Winblad B., Lannfelt L.;
"A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.";
Nat. Genet. 1:345-347(1992).
[106]
 VARIANT VAL-713.
DOI=10.1038/ng0792-306; PubMed=1307241 [NCBI, ExPASy, EBI, Israel, Japan]
Jones C.T., Morris S., Yates C.M., Moffoot A., Sharpe C., Brock D.J.H., St Clair D.;
"Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia.";
Nat. Genet. 1:306-309(1992).
[107]
 VARIANT AD1 THR-713.
DOI=10.1038/ng1292-255; PubMed=1303275 [NCBI, ExPASy, EBI, Israel, Japan]
Carter D.A., Desmarais E., Bellis M., Campion D., Clerget-Darpoux F., Brice A., Agid Y., Jaillard-Serradt A., Mallet J.;
"More missense in amyloid gene.";
Nat. Genet. 2:255-256(1992).
[108]
 VARIANTS AD1 ILE-717 AND PHE-717.
DOI=10.1006/bbrc.1993.2491; PubMed=8267572 [NCBI, ExPASy, EBI, Israel, Japan]
Liepnieks J.J., Ghetti B., Farlow M., Roses A.D., Benson M.D.;
"Characterization of amyloid fibril beta-peptide in familial Alzheimer's disease with APP717 mutations.";
Biochem. Biophys. Res. Commun. 197:386-392(1993).
[109]
 VARIANT ASP-665.
DOI=10.1002/ana.410350410; PubMed=8154870 [NCBI, ExPASy, EBI, Israel, Japan]
Peacock M.L., Murman D.L., Sima A.A.F., Warren J.T. Jr., Roses A.D., Fink J.K.;
"Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease.";
Ann. Neurol. 35:432-438(1994).
[110]
 VARIANT AD1 PHE-717.
PubMed=8290042 [NCBI, ExPASy, EBI, Israel, Japan]
Farlow M., Murrell J., Ghetti B., Unverzagt F., Zeldenrust S., Benson M.D.;
"Clinical characteristics in a kindred with early-onset Alzheimer's disease and their linkage to a G-->T change at position 2149 of the amyloid precursor protein gene.";
Neurology 44:105-111(1994).
[111]
 VARIANT AD1 ILE-717.
DOI=10.1016/0304-3940(95)12046-7; PubMed=8577393 [NCBI, ExPASy, EBI, Israel, Japan]
Brooks W.S., Martins R.N., De Voecht J., Nicholson G.A., Schofield P.R., Kwok J.B.J., Fisher C., Yeung L.U., Van Broeckhoven C.;
"A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease.";
Neurosci. Lett. 199:183-186(1995).
[112]
 VARIANT AD1 VAL-716.
DOI=10.1093/hmg/6.12.2087; PubMed=9328472 [NCBI, ExPASy, EBI, Israel, Japan]
Eckman C.B., Mehta N.D., Crook R., Perez-Tur J., Prihar G., Pfeiffer E., Graff-Radford N., Hinder P., Yager D., Zenk B., Refolo L.M., Prada C.M., Younkin S.G., Hutton M., Hardy J.;
"A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43).";
Hum. Mol. Genet. 6:2087-2089(1997).
[113]
 VARIANT AD1 GLY-692, AND CHARACTERIZATION OF PHENOTYPE.
DOI=10.1007/s004010050892; PubMed=9754958 [NCBI, ExPASy, EBI, Israel, Japan]
Cras P., van Harskamp F., Hendriks L., Ceuterick C., van Duijn C.M., Stefanko S.Z., Hofman A., Kros J.M., Van Broeckhoven C., Martin J.J.;
"Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation.";
Acta Neuropathol. 96:253-260(1998).
[114]
 VARIANT AD1 MET-715, AND CHARACTERIZATION OF VARIANT AD1 MET-715.
DOI=10.1073/pnas.96.7.4119; PubMed=10097173 [NCBI, ExPASy, EBI, Israel, Japan]
Ancolio K., Dumanchin C., Barelli H., Warter J.-M., Brice A., Campion D., Frebourg T., Checler F.;
"Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease.";
Proc. Natl. Acad. Sci. U.S.A. 96:4119-4124(1999).
[115]
 VARIANT AD1 ILE-717.
DOI=10.1086/302702; PubMed=10631141 [NCBI, ExPASy, EBI, Israel, Japan]
Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.;
"High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.";
Am. J. Hum. Genet. 66:110-117(2000).
[116]
 VARIANT AD1 PRO-723.
DOI=10.1002/1531-8249(200002)47:2<249::AID-ANA18>3.0.CO;2-8; PubMed=10665499 [NCBI, ExPASy, EBI, Israel, Japan]
Kwok J.B.J., Li Q.X., Hallupp M., Whyte S., Ames D., Beyreuther K., Masters C.L., Schofield P.R.;
"Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis.";
Ann. Neurol. 47:249-253(2000).
[117]
 VARIANT AD1 LEU-717.
DOI=10.1001/archneur.57.6.885; PubMed=10867787 [NCBI, ExPASy, EBI, Israel, Japan]
Murrell J.R., Hake A.M., Quaid K.A., Farlow M.R., Ghetti B.;
"Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene.";
Arch. Neurol. 57:885-887(2000).
[118]
 VARIANT AD1 ILE-714, CHARACTERIZATION OF VARIANT AD1 ILE-714, AND MUTAGENESIS OF VAL-717.
DOI=10.1093/hmg/9.18.2589; PubMed=11063718 [NCBI, ExPASy, EBI, Israel, Japan]
Kumar-Singh S., De Jonghe C., Cruts M., Kleinert R., Wang R., Mercken M., De Strooper B., Vanderstichele H., Loefgren A., Vanderhoeven I., Backhovens H., Vanmechelen E., Kroisel P.M., Van Broeckhoven C.;
"Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease.";
Hum. Mol. Genet. 9:2589-2598(2000).
[119]
 VARIANT AMYLCAIW ASN-694.
DOI=10.1002/ana.1009; PubMed=11409420 [NCBI, ExPASy, EBI, Israel, Japan]
Grabowski T.J., Cho H.S., Vonsattel J.P.G., Rebeck G.W., Greenberg S.M.;
"Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy.";
Ann. Neurol. 49:697-705(2001).
[120]
 CHARACTERIZATION OF VARIANT AD1 GLY-692.
PubMed=11311152 [NCBI, ExPASy, EBI, Israel, Japan]
Walsh D.M., Hartley D.M., Condron M.M., Selkoe D.J., Teplow D.B.;
"In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692-->Gly) Alzheimer's disease.";
Biochem. J. 355:869-877(2001).
[121]
 VARIANT AD1 GLY-693.
DOI=10.1038/nn0901-887; PubMed=11528419 [NCBI, ExPASy, EBI, Israel, Japan]
Nilsberth C., Westlind-Danielsson A., Eckman C.B., Condron M.M., Axelman K., Forsell C., Stenh C., Luthman J., Teplow D.B., Younkin S.G., Naeslund J., Lannfelt L.;
"The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.";
Nat. Neurosci. 4:887-893(2001).
[122]
 VARIANT AD1 ALA-714.
PubMed=12034808 [NCBI, ExPASy, EBI, Israel, Japan]
Pasalar P., Najmabadi H., Noorian A.R., Moghimi B., Jannati A., Soltanzadeh A., Krefft T., Crook R., Hardy J.;
"An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala).";
Neurology 58:1574-1575(2002).
[123]
 VARIANT AMYLCAIW ASN-694.
PubMed=12654973 [NCBI, ExPASy, EBI, Israel, Japan]
Greenberg S.M., Shin Y., Grabowski T.J., Cooper G.E., Rebeck G.W., Iglesias S., Chapon F., Tournier-Lasserve E., Baron J.-C.;
"Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation.";
Neurology 60:1020-1022(2003).
[124]
 VARIANT AD1 THR-713.
PubMed=15365148 [NCBI, ExPASy, EBI, Israel, Japan]
Rossi G., Giaccone G., Maletta R., Morbin M., Capobianco R., Mangieri M., Giovagnoli A.R., Bizzi A., Tomaino C., Perri M., Di Natale M., Tagliavini F., Bugiani O., Bruni A.C.;
"A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene.";
Neurology 63:910-912(2004).
[125]
 VARIANT AMYLCAIT VAL-705.
DOI=10.1002/ana.20571; PubMed=16178030 [NCBI, ExPASy, EBI, Israel, Japan]
Obici L., Demarchi A., de Rosa G., Bellotti V., Marciano S., Donadei S., Arbustini E., Palladini G., Diegoli M., Genovese E., Ferrari G., Coverlizza S., Merlini G.;
"A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy.";
Ann. Neurol. 58:639-644(2005).
[126]
 VARIANT AD1 ILE-714.
DOI=10.1212/01.WNL.0000149761.70566.3E; PubMed=15668448 [NCBI, ExPASy, EBI, Israel, Japan]
Edwards-Lee T., Ringman J.M., Chung J., Werner J., Morgan A., St George-Hyslop P.H., Thompson P., Dutton R., Mlikotic A., Rogaeva E., Hardy J.;
"An African American family with early-onset Alzheimer disease and an APP (T714I) mutation.";
Neurology 64:377-379(2005).
Comments
  • FUNCTION: Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-HTATIP and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity.
  • FUNCTION: Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity.
  • FUNCTION: Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).
  • FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.
  • SUBUNIT: Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and, Numb and Dab1 (By similarity). Binding to Dab1 inhibits its serine phosphorylation (By similarity). Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR domains) (By similarity), APPBP2 (via BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid beta-42 binds CHRNA7 in hippocampal neurons. Beta-amyloid associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with CPEB1 (By similarity). Interacts with ANKS1B.
  • INTERACTION:
    Self; NbExp=1; IntAct=EBI-77613, EBI-77613;
    Self; NbExp=2; IntAct=EBI-302641, EBI-302641;
    Q02410:APBA1; NbExp=2; IntAct=EBI-77613, EBI-368690;
    O00213:APBB1; NbExp=2; IntAct=EBI-77613, EBI-81694;
    P46933:Apbb1 (xeno); NbExp=1; IntAct=EBI-77613, EBI-286177;
    Q92870:APBB2; NbExp=1; IntAct=EBI-77613, EBI-79277;
    O35827:Apbb3 (xeno); NbExp=1; IntAct=EBI-77613, EBI-286163;
    P51693:APLP1; NbExp=1; IntAct=EBI-302641, EBI-74648;
    Q06481:APLP2; NbExp=1; IntAct=EBI-302641, EBI-79306;
    P02647:APOA1; NbExp=5; IntAct=EBI-77613, EBI-701692;
    P36544:CHRNA7; NbExp=1; IntAct=EBI-77613, EBI-79333;
    Q05941:Chrna7 (xeno); NbExp=1; IntAct=EBI-77613, EBI-79422;
    Q9P232:CNTN3; NbExp=1; IntAct=EBI-302641, EBI-2028361;
    Q8IWV2:CNTN4; NbExp=1; IntAct=EBI-302641, EBI-2028276;
    O75955:FLOT1; NbExp=4; IntAct=EBI-77613, EBI-603643;
    Q9NSB8:HOMER2; NbExp=1; IntAct=EBI-302661, EBI-2126733;
    Q9NSC5:HOMER3; NbExp=2; IntAct=EBI-302661, EBI-748420;
    Q99714:HSD17B10; NbExp=2; IntAct=EBI-77613, EBI-79964;
    Q9UQF2:MAPK8IP1; NbExp=3; IntAct=EBI-77613, EBI-78404;
    Q9WVI9-1:Mapk8ip1 (xeno); NbExp=1; IntAct=EBI-77613, EBI-288461;
    P10636:MAPT; NbExp=4; IntAct=EBI-77613, EBI-366182;
    P10636-8:MAPT; NbExp=1; IntAct=EBI-77613, EBI-366233;
    P08138:NGFR; NbExp=2; IntAct=EBI-77613, EBI-1387782;
    P04156:PRNP; NbExp=1; IntAct=EBI-77613, EBI-977302;
    P49768:PSEN1; NbExp=1; IntAct=EBI-77613, EBI-297277;
    P49768:PSEN1; NbExp=1; IntAct=EBI-302641, EBI-297277;
    P49768:PSEN1; NbExp=1; IntAct=EBI-302661, EBI-297277;
    P49810:PSEN2; NbExp=1; IntAct=EBI-77613, EBI-2010251;
    P29353:SHC1; NbExp=4; IntAct=EBI-77613, EBI-78835;
    Q92529:SHC3; NbExp=2; IntAct=EBI-77613, EBI-79084;
    Q8BGY9:Slc5a7 (xeno); NbExp=1; IntAct=EBI-77613, EBI-2010752;
    P01137:TGFB1; NbExp=1; IntAct=EBI-77613, EBI-779636;
    P61812:TGFB2; NbExp=2; IntAct=EBI-77613, EBI-779581;
    O75509:TNFRSF21; NbExp=3; IntAct=EBI-77613, EBI-2313231;
    Q13625:TP53BP2; NbExp=2; IntAct=EBI-77613, EBI-77642;
  • SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. Membrane, clathrin-coated pit. Note=Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment.
  • ALTERNATIVE PRODUCTS: 10 named isoforms [FASTA] produced by alternative splicing. Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.
    NameAPP770
    SynonymsPreA4 770
    Isoform IDP05067-1
    Note: A major isoform.
    This is the isoform sequence displayed in this entry.
    NameAPP305
    Isoform IDP05067-2
    Features which should be applied to build the isoform sequence: VSP_000005, VSP_000006.
    NameL-APP677
    Isoform IDP05067-3
    Note: The L-isoforms are referred to as appicans.
    Features which should be applied to build the isoform sequence: VSP_000002, VSP_000004, VSP_000009.
    NameAPP695
    SynonymsPreA4 695
    Isoform IDP05067-4
    Note: A major isoform.
    Features which should be applied to build the isoform sequence: VSP_000002, VSP_000004.
    NameL-APP696
    Isoform IDP05067-5
    Note: The L-isoforms are referred to as appicans.
    Features which should be applied to build the isoform sequence: VSP_000002, VSP_000003, VSP_000009.
    NameAPP714
    Isoform IDP05067-6
    Features which should be applied to build the isoform sequence: VSP_000002, VSP_000003.
    NameL-APP733
    Isoform IDP05067-7
    Note: The L-isoforms are referred to as appicans.
    Features which should be applied to build the isoform sequence: VSP_000007, VSP_000008, VSP_000009.
    NameAPP751
    SynonymsPreA4 751
    Isoform IDP05067-8
    Note: A major isoform.
    Features which should be applied to build the isoform sequence: VSP_000007, VSP_000008.
    NameL-APP752
    Isoform IDP05067-9
    Features which should be applied to build the isoform sequence: VSP_000009.
    NameAPP639
    Isoform IDP05067-10
    Features which should be applied to build the isoform sequence: VSP_009116, VSP_009117, VSP_009118.
  • TISSUE SPECIFICITY: Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex-opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra-striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes.
  • INDUCTION: Increased levels during neuronal differentiation.
  • DOMAIN: The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.
  • DOMAIN: The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The NPXY site is also involved in clathrin-mediated endocytosis.
  • PTM: Proteolytically processed under normal cellular conditions. Cleavage by alpha-secretase or alternatively by beta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, respectively, and the retention of corresponding membrane-anchored C-terminal fragments, C83 and C99. Subsequent processing of C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid beta proteins, amyloid-beta 40 (Abeta40) and amyloid-beta 42 (Abeta42), major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59).
  • PTM: Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-6, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides.
  • PTM: N- and O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core proteins, the appicans. The chondroitin sulfate chain of appicans contains 4-O-sulfated galactose in the linkage region and chondroitin sulfate E in the repeated disaccharide region (By similarity).
  • PTM: Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin.
  • PTM: Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an increased production of beta-amyloid-containing peptides.
  • MASS SPECTROMETRY: Mass=6461.6; Method=MALDI; Range=712-767; Source=PubMed:12214090;.
  • MASS SPECTROMETRY: Mass=6451.6; Method=MALDI; Range=714-770; Source=PubMed:12214090;.
  • MASS SPECTROMETRY: Mass=6436.8; Method=MALDI; Range=715-769; Source=PubMed:12214090;.
  • MASS SPECTROMETRY: Mass=5752.5; Method=MALDI; Range=719-767; Source=PubMed:12214090;.
  • DISEASE: Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:104300]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitve abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.
  • DISEASE: Defects in APP are the cause of amyloidosis cerebroarterial Dutch type (AMYLCAD) [MIM:605714]; also known as hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWAD). AMYLCAD is a hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. Beta-APP40 is the predominant form of cerebrovascular amyloid. Amyloid is not found outside the nervous system. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Onset of the disease is in middle age (44 to 60 years). Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease.
  • DISEASE: Defects in APP are the cause of amyloidosis cerebroarterial Italian type (AMYLCAIT) [MIM:605714]. AMYLCAIT is a hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels, resulting in cerebral amyloid angiopathy. Amyloid is not found outside the nervous system. It is a condition very similar to AMYLCAD, but the clinical course is less severe. Patients manifest mild cognitive decline, recurrent strokes, and epilepsy in some cases. There are extensive amyloid deposits in leptomeningeal and cortical vessels and, to a lesser extent, in the neuropil of the cerebral cortex, in the absence of neurofibrillary tangles.
  • DISEASE: Defects in APP are the cause of amyloidosis cerebroarterial Iowa type (AMYLCAIW) [MIM:605714]. AMYLCAIW is a hereditary amyloidosis due to amyloid-beta A4 peptide(s) deposition. Patients have progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.
  • MISCELLANEOUS: Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.
  • SIMILARITY: Belongs to the APP family.
  • SIMILARITY: Contains 1 BPTI/Kunitz inhibitor domain.
  • SEQUENCE CAUTION:
    • Sequence=AAA58727.1; Type=Miscellaneous discrepancy; Note=Contamination by an Alu repeat
  • WEB RESOURCE: Name=Alzheimer Research Forum; Note=APP mutations; URL="http://www.alzforum.org/res/com/mut/app/default.asp";.
  • WEB RESOURCE: Name=AD mutations; URL="http://www.molgen.ua.ac.be/ADmutations/";.
  • WEB RESOURCE: Name=GeneReviews; URL="http://www.genetests.org/query?gene=APP";.
  • WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/app/";.
  • WEB RESOURCE: Name=Wikipedia; Note=Amyloid beta entry; URL="http://en.wikipedia.org/wiki/Amyloid_beta";.
Copyright
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.
Cross-references
Sequence databases
EMBL
Y00264; CAA68374.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13466; CAA31830.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13467; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13468; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13469; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13470; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13471; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13472; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13473; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13474; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13475; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13476; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13477; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13478; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13479; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13487; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X13488; CAA31830.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X06989; CAA30050.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M33112; AAB59502.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34862; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34863; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34864; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34865; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34866; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34867; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34868; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34869; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34870; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34871; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34872; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34873; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34874; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34876; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34877; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34878; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34879; AAB59502.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34875; AAB59501.1; ALT_TERM; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34862; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34863; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34864; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34865; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34866; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34867; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34868; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34869; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34870; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34871; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34872; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M34873; AAB59501.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
D87675; BAA22264.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AY919674; AAW82435.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
CH471079; EAX09958.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC004369; AAH04369.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC065529; AAH65529.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M35675; AAA60163.1; ALT_SEQ; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M24547; AAC13654.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M24546; AAC13654.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M28373; AAA58727.1; ALT_SEQ; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M16765; AAA51722.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X06982; CAA30042.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
X06981; CAA30041.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M18734; AAA51726.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M29270; AAA51768.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M29269; AAA51768.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AB066441; BAB71958.2; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M15533; AAA35540.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M15532; AAA51564.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M37896; AAA51727.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
M37895; AAA51727.1; JOINED; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
S45136; AAB23646.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
S60317; AAC60601.2; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF282245; AAQ14327.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
S60721; AAB26263.2; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
S61380; AAB26264.2; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
S61383; AAB26265.2; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
IPI IPI00006608; -.
IPI00219182; -.
IPI00219183; -.
IPI00219185; -.
IPI00219186; -.
IPI00219187; -.
IPI00394658; -.
IPI00412568; -.
IPI00412681; -.
IPI00412924; -.
PIR S01442; S01442.
S02260; QRHUA4.
RefSeq NP_000475.1; -.
NP_001129601.1; -.
NP_958816.1; -.
NP_958817.1; -.
UniGene Hs.434980
3D structure databases
PDB
1AAP; X-ray; 1.50 A; A/B=287-344.[ExPASy / RCSB / EBI]
1AMB; NMR; -; A=672-699.[ExPASy / RCSB / EBI]
1AMC; NMR; -; A=672-699.[ExPASy / RCSB / EBI]
1AML; NMR; -; A=672-711.[ExPASy / RCSB / EBI]
1BA4; NMR; -; A=672-711.[ExPASy / RCSB / EBI]
1BA6; NMR; -; A=672-711.[ExPASy / RCSB / EBI]
1BJB; NMR; -; A=672-699.[ExPASy / RCSB / EBI]
1BJC; NMR; -; A=672-699.[ExPASy / RCSB / EBI]
1BRC; X-ray; 2.50 A; I=287-342.[ExPASy / RCSB / EBI]
1CA0; X-ray; 2.10 A; D/I=289-342.[ExPASy / RCSB / EBI]
1HZ3; NMR; -; A=681-706.[ExPASy / RCSB / EBI]
1IYT; NMR; -; A=672-713.[ExPASy / RCSB / EBI]
1MWP; X-ray; 1.80 A; A=28-123.[ExPASy / RCSB / EBI]
1OWT; NMR; -; A=124-189.[ExPASy / RCSB / EBI]
1QCM; NMR; -; A=696-706.[ExPASy / RCSB / EBI]
1QWP; NMR; -; A=696-706.[ExPASy / RCSB / EBI]
1QXC; NMR; -; A=696-706.[ExPASy / RCSB / EBI]
1QYT; NMR; -; A=696-706.[ExPASy / RCSB / EBI]
1RW6; X-ray; 2.80 A; A=365-570.[ExPASy / RCSB / EBI]
1TAW; X-ray; 1.80 A; B=287-344.[ExPASy / RCSB / EBI]
1TKN; NMR; -; A=460-569.[ExPASy / RCSB / EBI]
1UO7; Model; -; A=672-713.[ExPASy / RCSB / EBI]
1UO8; Model; -; A=672-713.[ExPASy / RCSB / EBI]
1UOA; Model; -; A=672-713.[ExPASy / RCSB / EBI]
1UOI; Model; -; A=672-713.[ExPASy / RCSB / EBI]
1X11; X-ray; 2.50 A; C/D=754-766.[ExPASy / RCSB / EBI]
1Z0Q; NMR; -; A=672-713.[ExPASy / RCSB / EBI]
1ZE7; NMR; -; A=672-687.[ExPASy / RCSB / EBI]
1ZE9; NMR; -; A=672-687.[ExPASy / RCSB / EBI]
1ZJD; X-ray; 2.60 A; B=289-344.[ExPASy / RCSB / EBI]
2BEG; NMR; -; A/B/C/D/E=672-713.[ExPASy / RCSB / EBI]
2BOM; Model; -; A/B=681-713.[ExPASy / RCSB / EBI]
2BP4; NMR; -; A=672-687.[ExPASy / RCSB / EBI]
2FJZ; X-ray; 1.61 A; A=133-189.[ExPASy / RCSB / EBI]
2FK1; X-ray; 1.60 A; A=133-189.[ExPASy / RCSB / EBI]
2FK2; X-ray; 1.65 A; A=133-189.[ExPASy / RCSB / EBI]
2FK3; X-ray; 2.40 A; A/B/C/D/E/F/G/H=133-189.[ExPASy / RCSB / EBI]
2FKL; X-ray; 2.50 A; A/B=124-189.[ExPASy / RCSB / EBI]
2FMA; X-ray; 0.85 A; A=133-189.[ExPASy / RCSB / EBI]
2G47; X-ray; 2.10 A; C/D=672-711.[ExPASy / RCSB / EBI]
2IPU; X-ray; 1.65 A; P/Q=672-679.[ExPASy / RCSB / EBI]
2OTK; NMR; -; C=672-711.[ExPASy / RCSB / EBI]
2R0W; X-ray; 2.50 A; Q=672-679.[ExPASy / RCSB / EBI]
3DXC; X-ray; 2.10 A; B/D=739-770.[ExPASy / RCSB / EBI]
3DXD; X-ray; 2.20 A; B/D=739-770.[ExPASy / RCSB / EBI]
3DXE; X-ray; 2.00 A; B/D=739-770.[ExPASy / RCSB / EBI]
3GCI; X-ray; 2.04 A; P=707-713.[ExPASy / RCSB / EBI]
Detailed list of linked structures.
PDBsum 1AAP; -.
1AMB; -.
1AMC; -.
1AML; -.
1BA4; -.
1BA6; -.
1BJB; -.
1BJC; -.
1BRC; -.
1CA0; -.
1HZ3; -.
1IYT; -.
1MWP; -.
1OWT; -.
1QCM; -.
1QWP; -.
1QXC; -.
1QYT; -.
1RW6; -.
1TAW; -.
1TKN; -.
1UO7; -.
1UO8; -.
1UOA; -.
1UOI; -.
1X11; -.
1Z0Q; -.
1ZE7; -.
1ZE9; -.
1ZJD; -.
2BEG; -.
2BOM; -.
2BP4; -.
2FJZ; -.
2FK1; -.
2FK2; -.
2FK3; -.
2FKL; -.
2FMA; -.
2G47; -.
2IPU; -.
2OTK; -.
2R0W; -.
3DXC; -.
3DXD; -.
3DXE; -.
3GCI; -.
ModBase P05067.
Protein-protein interaction databases
DIP DIP:574N; -.
IntAct P05067; 57.
Protein family/group databases
MEROPS I02.015; -.
PTM databases
GlycoSuiteDB P05067; -.
PhosphoSite P05067; -.
Enzyme and pathway databases
Pathway_Interaction_DB caspase_pathway; Caspase cascade in apoptosis.
glypican_1pathway; Glypican 1 network.
p75ntrpathway; p75(NTR)-mediated signaling.
Reactome REACT_604; Hemostasis.
2D gel databases
SWISS-2DPAGE P05067; -.
Organism-specific databases
GeneCards GC21M026174; -.
H-InvDB HIX0040845; -.
HGNC HGNC:620; APP.
GenAtlas APP.
HPA CAB000157; -.
HPA001462; -.
MIM 104300; phenotype. [NCBI / EBI]
104760; gene+phenotype. [NCBI / EBI]
605714; phenotype. [NCBI / EBI]
Orphanet 1020; Alzheimer disease, familial.
85458; Cerebral hemorrhage with amyloidosis, hereditary.
PharmGKB PA24910; -.
Gene expression databases
ArrayExpress P05067; -.
Bgee P05067; -.
GermOnline ENSG00000142192; Homo sapiens.
Ontologies
GO
GO:0009986; Cellular component: cell surface (inferred from direct assay from UniProtKB).
GO:0005905; Cellular component: coated pit (inferred from electronic annotation from UniProtKB-SubCell).
GO:0005576; Cellular component: extracellular region (inferred from experiment from Reactome).
GO:0005794; Cellular component: Golgi apparatus (inferred from direct assay from HPA).
GO:0005887; Cellular component: integral to plasma membrane (traceable author statement from ProtInc).
GO:0031093; Cellular component: platelet alpha granule lumen (inferred from experiment from Reactome).
GO:0033130; Molecular function: acetylcholine receptor binding (inferred from physical interaction from UniProtKB).
GO:0005507; Molecular function: copper ion binding (inferred from electronic annotation from UniProtKB-KW).
GO:0008201; Molecular function: heparin binding (inferred from electronic annotation from UniProtKB-KW).
GO:0042802; Molecular function: identical protein binding (inferred from physical interaction from IntAct).
GO:0005506; Molecular function: iron ion binding (inferred from electronic annotation from UniProtKB-KW).
GO:0004867; Molecular function: serine-type endopeptidase inhibitor activity (inferred from direct assay from UniProtKB).
GO:0008270; Molecular function: zinc ion binding (inferred from electronic annotation from UniProtKB-KW).
GO:0006915; Biological process: apoptosis (inferred from electronic annotation from UniProtKB-KW).
GO:0007155; Biological process: cell adhesion (inferred from electronic annotation from UniProtKB-KW).
GO:0006878; Biological process: cellular copper ion homeostasis (traceable author statement from UniProtKB).
GO:0006897; Biological process: endocytosis (inferred from electronic annotation from UniProtKB-KW).
GO:0050905; Biological process: neuromuscular process (non-traceable author statement from UniProtKB).
GO:0007219; Biological process: Notch signaling pathway (inferred from electronic annotation from UniProtKB-KW).
QuickGo view.
Family and domain databases
InterPro IPR008155; Amyloid_glyco.
IPR013803; Amyloid_glyco_Abeta.
IPR011178; Amyloid_glyco_Cu-bd.
IPR008154; Amyloid_glyco_extra.
IPR019744; Amyloid_glyco_extracell_CS.
IPR015849; Amyloid_glyco_heparin-bd.
IPR019745; Amyloid_glyco_intracell_CS.
IPR019543; APP_amyloid.
IPR002223; Prot_inh_Kunz-m.
Graphical view of domain structure.
Gene3D G3DSA:4.10.230.10; Amyloid_glyco_Abeta; 1.
G3DSA:3.30.1490.140; Amyloid_glyco_Cu-bd; 1.
G3DSA:3.90.570.10; Amyloid_glyco_heparin-bd; 1.
G3DSA:4.10.410.10; Prot_inh_Kunz-m; 1.
Pfam PF02177; A4_EXTRA; 1.
PF10515; APP_amyloid; 1.
PF03494; Beta-APP; 1.
PF00014; Kunitz_BPTI; 1.
Pfam graphical view of domain structure.
PRINTS PR00203; AMYLOIDA4.
PR00204; BETAAMYLOID.
ProDom PD000222; Prot_Inh_Kunz-m; 1.
[Domain structure / List of seq. sharing at least 1 domain]
SMART SM00006; A4_EXTRA; 1.
SM00131; KU; 1.
SMART graphical view of domain structure.
PROSITE PS00319; A4_EXTRA; 1.
PS00320; A4_INTRA; 1.
PS00280; BPTI_KUNITZ_1; 1.
PS50279; BPTI_KUNITZ_2; 1.
PROSITE graphical view of domain structure (profiles).
Other
SWISS-3DIMAGE P05067.
Proteomic databases
PRIDE P05067; -.
Genome annotation databases
Ensembl ENSG00000142192; Homo sapiens. [Contig view]
GeneID 351; -.
KEGG hsa:351; -.
Phylogenomic databases
HOVERGEN P05067; -.
OMA P05067; QEAANER.
Other
NextBio 1445; -.
PMAP-CutDB P05067; -.
SOURCE APP; Homo sapiens.
ProtoNet P05067.
UniRef View cluster of proteins with at least 50% / 90% / 100% identity.
Keywords
3D-structure; Alternative splicing; Alzheimer disease; Amyloid; Amyloidosis; Apoptosis; Cell adhesion; Coated pit; Copper; Direct protein sequencing; Disease mutation; Disulfide bond; Endocytosis; Glycoprotein; Heparin-binding; Iron; Membrane; Metal-binding; Neurodegeneration; Notch signaling pathway; Phosphoprotein; Polymorphism; Protease inhibitor; Proteoglycan; Serine protease inhibitor; Signal; Transmembrane; Zinc.
Features
SEVIEWER logo Feature table viewer FT aligner logo Feature aligner
KeyFrom   To Length Description FTId
SIGNAL   1    17  17      
CHAIN   18   770  753     Amyloid beta A4 protein. PRO_0000000088
CHAIN   18   687  670     Soluble APP-alpha. PRO_0000000089
CHAIN   18   671  654     Soluble APP-beta. PRO_0000000090
CHAIN   672   770  99     C99. PRO_0000000091
CHAIN   672   713  42     Beta-amyloid protein 42. PRO_0000000092
CHAIN   672   711  40     Beta-amyloid protein 40. PRO_0000000093
CHAIN   688   770  83     C83. PRO_0000000094
PEPTIDE   688   713  26     P3(42). PRO_0000000095
PEPTIDE   688   711  24     P3(40). PRO_0000000096
CHAIN   712   770  59     Gamma-secretase C-terminal fragment 59. PRO_0000000097
CHAIN   714   770  57     Gamma-secretase C-terminal fragment 57. PRO_0000000098
CHAIN   721   770  50     Gamma-secretase C-terminal fragment 50 (By similarity). PRO_0000000099
CHAIN   740   770  31     C31. PRO_0000000100
TOPO_DOM   18   699  682     Extracellular (Potential). 
TRANSMEM   700   723  24     Potential. 
TOPO_DOM   724   770  47     Cytoplasmic (Potential). 
DOMAIN   291   341  51     BPTI/Kunitz inhibitor. 
REGION   96   110  15     Heparin-binding. 
REGION   181   188  8     Zinc-binding. 
REGION   391   423  33     Heparin-binding. 
REGION   491   522  32     Heparin-binding. 
REGION   523   540  18     Collagen-binding. 
REGION   732   751  20     Interaction with G(o)-alpha. 
MOTIF   724   734  11     Basolateral sorting signal. 
MOTIF   759   762  4     NPXY motif; contains endocytosis signal. 
COMPBIAS   230   260  31     Asp/Glu-rich (acidic). 
COMPBIAS   274   280  7     Poly-Thr. 
METAL   137   137        Copper. 
METAL   147   147        Copper. 
METAL   149   149        Copper. 
METAL   151   151        Copper (Probable). 
METAL   677   677        Copper or zinc. 
METAL   681   681        Copper or zinc (Probable). 
METAL   684   684        Copper or zinc. 
METAL   685   685        Copper or zinc. 
SITE   144   144  1     Required for Cu(2+) reduction. 
SITE   301   302  2     Reactive bond. 
SITE   671   672  2     Cleavage; by beta-secretase. 
SITE   672   673  2     Cleavage; by caspase-6; when associated with variant 670-N-L-671. 
SITE   687   688  2     Cleavage; by alpha-secretase. 
SITE   704   704  1     Implicated in free radical propagation (By similarity). 
SITE   706   706  1     Susceptible to oxidation. 
SITE   711   712  2     Cleavage; by gamma-secretase; site 1. 
SITE   713   714  2     Cleavage; by gamma-secretase; site 2. 
SITE   720   721  2     Cleavage; by gamma-secretase; site 3. 
SITE   739   740  2     Cleavage; by caspase-6, caspase-8 or caspase-9. 
MOD_RES   198   198        Phosphoserine; by CK2. 
MOD_RES   206   206        Phosphoserine; by CK1. 
MOD_RES   729   729        Phosphothreonine (By similarity). 
MOD_RES   730   730        Phosphoserine; by APP-kinase I (By similarity). 
MOD_RES   743   743        Phosphothreonine; by CDK5 and MAPK10. 
MOD_RES   757   757        Phosphotyrosine. 
MOD_RES   762   762        Phosphotyrosine. 
CARBOHYD   542   542        N-linked (GlcNAc...). 
CARBOHYD   571   571        N-linked (GlcNAc...) (Probable). 
CARBOHYD   656   656        O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms. 
DISULFID   144   158         
DISULFID   291   341         
DISULFID   300   324         
DISULFID   316   337         
VAR_SEQ   19    74        Missing (in isoform APP639). VSP_009116
VAR_SEQ   289   363        Missing (in isoform APP639). VSP_009117
VAR_SEQ   289   289        E -> V (in isoform APP695, isoform L-APP696, isoform L-APP677 and isoform APP714). VSP_000002
VAR_SEQ   290   364        Missing (in isoform APP695 and isoform L-APP677). VSP_000004
VAR_SEQ   290   345        Missing (in isoform L-APP696 and isoform APP714). VSP_000003
VAR_SEQ   290   305        VCSEQAETGPCRAMIS -> KWYKEVHSGQARWLML (in isoform APP305). VSP_000005
VAR_SEQ   306   770        Missing (in isoform APP305). VSP_000006
VAR_SEQ   345   345        M -> I (in isoform L-APP733 and isoform APP751). VSP_000007
VAR_SEQ   346   364        Missing (in isoform L-APP733 and isoform APP751). VSP_000008
VAR_SEQ   364   364        L -> V (in isoform APP639). VSP_009118
VAR_SEQ   637   654        Missing (in isoform L-APP677, isoform L-APP696, isoform L-APP733 and isoform L-APP752). VSP_000009
VARIANT   501   501  1     E -> K. VAR_022315 
VARIANT   665   665  1     E -> D (in a patient with late onset Alzheimer disease). VAR_010107 
VARIANT   670   671  2     KM -> NL (in AD1). VAR_000015
VARIANT   678   678  1     D -> N (in AD1). VAR_044424 
VARIANT   692   692  1     A -> G (in AD1; Flemish mutation; increases the solubility of processed beta-amyloid peptides and increases the stability of peptide oligomers). VAR_000016 
VARIANT   693   693  1     E -> G (in AD1). VAR_014215 
VARIANT   693   693  1     E -> K (in AMYLCAIT). VAR_014216 
VARIANT   693   693  1     E -> Q (in AMYLCAD). VAR_000017 
VARIANT   694   694  1     D -> N (in AMYLCAIW). VAR_014217 
VARIANT   705   705  1     L -> V (in AMYLCAIT). VAR_032276 
VARIANT   713   713  1     A -> T (in AD1). VAR_000019 
VARIANT   713   713  1     A -> V (in one chronic schizophrenia patient; could be a polymorphism; dbSNP:rs1800557 [NCBI]). VAR_000018 
VARIANT   714   714  1     T -> A (in AD1). VAR_032277 
VARIANT   714   714  1     T -> I (in AD1; increased beta-APP42/beta-APP40 ratio). VAR_014218 
VARIANT   715   715  1     V -> M (in AD1; decreased beta-APP40/total APP-beta). VAR_010108 
VARIANT   716   716  1     I -> V (in AD1). VAR_000020 
VARIANT   717   717  1     V -> F (in AD1). VAR_000023 
VARIANT   717   717  1     V -> G (in AD1). VAR_000022 
VARIANT   717   717  1     V -> I (in AD1). VAR_000021 
VARIANT   717   717  1     V -> L (in AD1). VAR_014219 
VARIANT   723   723  1     L -> P (in AD1). VAR_010109 
MUTAGEN   99   102        KRGR->NQGG: Reduced heparin-binding. 
MUTAGEN   137   137        H->N: Binds copper. Forms dimer. 
MUTAGEN   141   141        M->T: Binds copper. Forms dimer. 
MUTAGEN   144   144        C->S: Binds copper. No dimer formation. No copper reducing activity. 
MUTAGEN   147   149        HLH->ALA: 50% decrease in copper reducing activity. 
MUTAGEN   147   147        H->A: Some decrease in copper reducing activity. 
MUTAGEN   147   147        H->N: Binds copper. Forms dimer. 
MUTAGEN   147   147        H->Y: Greatly reduced copper-mediated low-density lipoprotein oxidation. 
MUTAGEN   151   151        H->K: Greatly reduced copper-mediated low-density lipoprotein oxidation. 
MUTAGEN   151   151        H->N: Binds copper. Forms dimer. 
MUTAGEN   198   198        S->A: Greatly reduced casein kinase phosphorylation. 
MUTAGEN   206   206        S->A: Reduced casein kinase phosphorylation. 
MUTAGEN   499   499        R->A: Reduced affinity for heparin; when associated with A-503. 
MUTAGEN   503   503        K->A: Reduced affinity for heparin; when associated with A-499. 
MUTAGEN   656   656        S->A: Abolishes chondroitin sulfate binding in L-APP733 isoform. 
MUTAGEN   676   676        R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation. 
MUTAGEN   681   681        Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation. 
MUTAGEN   684   684        H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation. 
MUTAGEN   704   704        G->V: Reduced protein oxidation. No hippocampal neuron toxicity. 
MUTAGEN   706   706        M->L: Reduced lipid peroxidation inhibition. 
MUTAGEN   706   706        M->V: No free radical production. No hippocampal neuron toxicity. 
MUTAGEN   717   717        V->C,S: Unchanged beta-APP42/total APP-beta ratio. 
MUTAGEN   717   717        V->F,G,I: Increased beta-APP42/beta-APP40 ratio. 
MUTAGEN   717   717        V->K: Decreased beta-APP42/total APP-beta ratio. 
MUTAGEN   717   717        V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage. 
MUTAGEN   728   728        Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion. 
MUTAGEN   739   739        D->A: No cleavage by caspases during apoptosis. 
MUTAGEN   739   739        D->N: No effect on FADD-induced apoptosis. 
MUTAGEN   743   743        T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension. 
MUTAGEN   743   743        T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation. 
MUTAGEN   756   756        G->A: APP internalization unchanged. No change in beta-APP42 secretion. 
MUTAGEN   757   757        Y->A: Little APP internalization. Reduced beta-APP42 secretion. 
MUTAGEN   757   757        Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1. 
MUTAGEN   759   759        N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion. 
MUTAGEN   760   760        P->A: Little APP internalization. Reduced beta-APP42 secretion. 
MUTAGEN   762   762        Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion. 
CONFLICT   15    16        AR -> VW (in Ref. 3; CAA31830). 
CONFLICT   647   647        D -> E (in Ref. 18; AAA51722). 
CONFLICT   724   724        Missing (in Ref. 23; AAB26263/AAB26264). 
CONFLICT   731   731        I -> N (in Ref. 23; AAB26263/AAB26264/AAB26265). 
CONFLICT   757   757        Y -> S (in Ref. 31; AAA35540). 
STRAND   33    35  3      
STRAND   43    45  3      
TURN   47    49  3      
STRAND   52    54  3      
HELIX   66    76  11      
STRAND   82    87  6      
STRAND   92    94  3      
STRAND   97    99  3      
HELIX   100   102  3      
STRAND   103   106  4      
STRAND   110   112  3      
STRAND   115   119  5      
STRAND   134   139  6      
HELIX   147   160  14      
STRAND   163   174  12      
TURN   175   177  3      
STRAND   178   188  11      
HELIX   288   292  5      
STRAND   299   301  3      
STRAND   304   310  7      
TURN   311   314  4      
STRAND   315   321  7      
STRAND   323   325  3      
STRAND   331   333  3      
HELIX   334   341  8      
HELIX   461   482  22      
HELIX   487   518  32      
HELIX   520   549  30      
HELIX   552   566  15      
HELIX   680   697  18      
HELIX   703   706  4      
TURN   707   710  4      
Sequence information
Length: 770 AA [This is the length of the unprocessed precursor] Molecular weight: 86943 Da [This is the MW of the unprocessed precursor] CRC64: A12EE761403740F5 [This is a checksum on the sequence] 
        10         20         30         40         50         60 
MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK 

        70         80         90        100        110        120 
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG 

       130        140        150        160        170        180 
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR 

       190        200        210        220        230        240 
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE 

       250        260        270        280        290        300 
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC 

       310        320        330        340        350        360 
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD 

       370        380        390        400        410        420 
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA 

       430        440        450        460        470        480 
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL 

       490        500        510        520        530        540 
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER 

       550        560        570        580        590        600 
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET 

       610        620        630        640        650        660 
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN 

       670        680        690        700        710        720 
IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL 

       730        740        750        760        770 
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
P05067 in FASTA format

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