UniProtKB/Swiss-Prot Q5S007: Variant p.Gly2385Arg

Leucine-rich repeat serine/threonine-protein kinase 2
Gene: LRRK2
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Variant information Variant position:

2385 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LP/P [Disclaimer] The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Glycine (G) to Arginine (R) at position 2385 (G2385R, p.Gly2385Arg). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties:

Change from glycine (G) to large size and basic (R) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-2 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:

Lowest score: -4 (low probability of substitution).
Highest score: 11 (high probability of substitution).

More information can be found on the following page
Variant description:

In PARK8; under conditions of oxidative stress the variant protein is more toxic and is correlated with a higher rate of apoptosis; reduced binding to synaptic vesicles; no loss of interaction with SEC16A; shows an increase in activity in phosphorylation of RAB8A and RAB10; shows decreased WD domain homodimerization; reduced autophosphorylation at Ser-935. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs34778348 [ dbSNP | Ensembl ]

Sequence information Variant position:

2385 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

2527 The length of the canonical sequence.
Location on the sequence:

IAKQNSPVVEVWDKKTEKLC G LIDCVHFLREVMVKENKESK The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Residue conservation:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         IAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKENKESK

Mouse                         IAKKNSPVVEVWDKKTEKLCELIDCVHFLKEVMVKLNKESK

Sequence annotation in neighborhood:

The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:

Type: the type of sequence feature.
Positions: endpoints of the sequence feature.
Description: contains additional information about the feature.

Type	Positions	Description
Chain	1 – 2527	Leucine-rich repeat serine/threonine-protein kinase 2
Mutagenesis	2391 – 2391	H -> D. Increases kinase activity.
Mutagenesis	2394 – 2394	R -> E. Decreases WD domain homodimerization. Increases kinase activity and autophosphorylation at Ser-1292.
Mutagenesis	2395 – 2395	E -> R. Decreases WD domain homodimerization. No effect on kinase activity.
Beta strand	2382 – 2388

Literature citations
Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
Piccoli G.; Onofri F.; Cirnaru M.D.; Kaiser C.J.; Jagtap P.; Kastenmuller A.; Pischedda F.; Marte A.; von Zweydorf F.; Vogt A.; Giesert F.; Pan L.; Antonucci F.; Kiel C.; Zhang M.; Weinkauf S.; Sattler M.; Sala C.; Matteoli M.; Ueffing M.; Gloeckner C.J.;
Mol. Cell. Biol. 34:2147-2161(2014)
Cited for: FUNCTION; SUBCELLULAR LOCATION; ELECTRON MICROSCOPY; WD REPEATS; CHARACTERIZATION OF VARIANT ARG-2385; Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.
Steger M.; Tonelli F.; Ito G.; Davies P.; Trost M.; Vetter M.; Wachter S.; Lorentzen E.; Duddy G.; Wilson S.; Baptista M.A.; Fiske B.K.; Fell M.J.; Morrow J.A.; Reith A.D.; Alessi D.R.; Mann M.;
Elife 5:0-0(2016)
Cited for: FUNCTION; CATALYTIC ACTIVITY; COFACTOR; ACTIVITY REGULATION; INTERACTION WITH RAB8A; RAB10 AND RAB12; CHARACTERIZATION OF VARIANTS PARK8 HIS-1441; CYS-1441; GLY-1441; CYS-1699; HIS-1728; SER-2019; THR-2020; SER-2031 AND ARG-2385; MUTAGENESIS OF ASP-1994; Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.
Purlyte E.; Dhekne H.S.; Sarhan A.R.; Gomez R.; Lis P.; Wightman M.; Martinez T.N.; Tonelli F.; Pfeffer S.R.; Alessi D.R.;
EMBO J. 37:1-18(2018)
Cited for: FUNCTION; CATALYTIC ACTIVITY; ACTIVITY REGULATION; SUBCELLULAR LOCATION; PHOSPHORYLATION AT SER-910; SER-935; SER-955; SER-973 AND SER-1292; CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; CYS-1699; HIS-1728; SER-2019; THR-2020; SER-2031 AND ARG-2385; MUTAGENESIS OF CYS-727; LEU-728; LEU-729; LEU-760; LEU-761; LEU-762; LEU-789; LEU-790; LEU-791; THR-1348; ARG-1441; TYR-1699; ASP-2017 AND GLY-2019; Crystal structure of the WD40 domain dimer of LRRK2.
Zhang P.; Fan Y.; Ru H.; Wang L.; Magupalli V.G.; Taylor S.S.; Alessi D.R.; Wu H.;
Proc. Natl. Acad. Sci. U.S.A. 116:1579-1584(2019)
Cited for: X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 2142-2527; FUNCTION; CATALYTIC ACTIVITY; SUBUNIT; DOMAIN; PHOSPHORYLATION AT SER-935 AND SER-1292; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; SER-2019; ASP-2175; TYR-2189; ILE-2356; ARG-2385; MET-2390 AND ILE-2439; MUTAGENESIS OF ASP-2017; LEU-2343; PHE-2344; SER-2345; TYR-2346; HIS-2391; ARG-2394; GLU-2395; MET-2408 AND SER-2409; Lrrk2 pathogenic substitutions in Parkinson's disease.
Mata I.F.; Kachergus J.M.; Taylor J.P.; Lincoln S.; Aasly J.; Lynch T.; Hulihan M.M.; Cobb S.A.; Wu R.-M.; Lu C.-S.; Lahoz C.; Wszolek Z.K.; Farrer M.J.;
Neurogenetics 6:171-177(2005)
Cited for: VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; GLN-1514; SER-1542; GLU-1598; PRO-1628; CYS-1699; THR-1869; THR-2012; SER-2019; THR-2020 AND ARG-2385; VARIANTS PRO-119; LYS-551; VAL-723; MET-793; VAL-1122; ALA-1262; HIS-1398; THR-1646; THR-1647; ASP-2081; LEU-2119; ILE-2261 AND THR-2397; The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence.
Tan E.K.; Zhao Y.; Skipper L.; Tan M.G.; Di Fonzo A.; Sun L.; Fook-Chong S.; Tang S.; Chua E.; Yuen Y.; Tan L.; Pavanni R.; Wong M.C.; Kolatkar P.; Lu C.S.; Bonifati V.; Liu J.J.;
Hum. Genet. 120:857-863(2007)
Cited for: CHARACTERIZATION OF VARIANT ARG-2385; ASSOCIATION WITH PARKINSON DISEASE; Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease.
Bardien S.; Lesage S.; Brice A.; Carr J.;
Parkinsonism Relat. Disord. 17:501-508(2011)
Cited for: VARIANTS PARK8 PRO-1628 AND ARG-2385; Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
Cho H.J.; Yu J.; Xie C.; Rudrabhatla P.; Chen X.; Wu J.; Parisiadou L.; Liu G.; Sun L.; Ma B.; Ding J.; Liu Z.; Cai H.;
EMBO J. 33:2314-2331(2014)
Cited for: CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; CYS-1699 AND SER-2019; CHARACTERIZATION OF VARIANT ARG-2385; FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH SEC16A; MUTAGENESIS OF LYS-1347 AND ASP-1994;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.