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UniProtKB/Swiss-Prot Q5S007: Variant p.Arg1441Cys

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

Variant position:  1441
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Cysteine (C) at position 1441 (R1441C, p.Arg1441Cys).
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 large size and basic (R) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
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

Involvement in disease:  Parkinson disease 8 (PARK8) [MIM:607060]: A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. {ECO:0000269|PubMed:15541308, ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:16333314, ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18213618, ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28202711, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In PARK8; shows an increase in activity in both autophosphorylation and phosphorylation of a generic substrate; loss of interaction with SEC16A; shows an increase in activity in phosphorylation of RAB10; decreases phosphorylation-dependent binding to YWHAG.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  1441
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:   LSKGQAEVDAMKPWLFNIKA  R ASSSPVILVGTHLDVSDEKQ
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                         LSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQ

Mouse                         LSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQ

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.

TypePositionsDescription
Chain 1 – 2527 Leucine-rich repeat serine/threonine-protein kinase 2
Domain 1328 – 1511 Roc
Modified residue 1444 – 1444 Phosphoserine
Mutagenesis 1441 – 1441 R -> G. Decreased membrane association when associated with D-727, D-728, or D-729. Inhibits autophosphorylation and RAB10 phosphorylation when associated with N-1348 or A-2017.
Helix 1431 – 1441


Literature citations

Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
Zimprich A.; Biskup S.; Leitner P.; Lichtner P.; Farrer M.; Lincoln S.J.; Kachergus J.M.; Hulihan M.M.; Uitti R.J.; Calne D.B.; Stoessl A.J.; Pfeiffer R.F.; Patenge N.; Carballo Carbajal I.; Vieregge P.; Asmus F.; Mueller-Myhsok B.; Dickson D.W.; Meitinger T.; Strom T.M.; Wszolek Z.K.; Gasser T.;
Neuron 44:601-607(2004)
Cited for: NUCLEOTIDE SEQUENCE [MRNA]; TISSUE SPECIFICITY; VARIANTS PARK8 VAL-1122; CYS-1441; CYS-1699 AND THR-2020;

Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
West A.B.; Moore D.J.; Biskup S.; Bugayenko A.; Smith W.W.; Ross C.A.; Dawson V.L.; Dawson T.M.;
Proc. Natl. Acad. Sci. U.S.A. 102:16842-16847(2005)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS PARK8 CYS-1441 AND SER-2019;

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 AND ASP-2017;

Structural interface between LRRK2 and 14-3-3 protein.
Stevers L.M.; de Vries R.M.; Doveston R.G.; Milroy L.G.; Brunsveld L.; Ottmann C.;
Biochem. J. 474:1273-1287(2017)
Cited for: X-RAY CRYSTALLOGRAPHY (1.33 ANGSTROMS) OF 929-941 IN COMPLEX WITH SFN; INTERACTION WITH YWHAG; PHOSPHORYLATION AT SER-910; SER-935; SER-955; SER-973 AND SER-1444; CHARACTERIZATION OF VARIANT PARK8 CYS-1441;

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.
Di Fonzo A.; Tassorelli C.; De Mari M.; Chien H.F.; Ferreira J.; Rohe C.F.; Riboldazzi G.; Antonini A.; Albani G.; Mauro A.; Marconi R.; Abbruzzese G.; Lopiano L.; Fincati E.; Guidi M.; Marini P.; Stocchi F.; Onofrj M.; Toni V.; Tinazzi M.; Fabbrini G.; Lamberti P.; Vanacore N.; Meco G.; Leitner P.; Uitti R.J.; Wszolek Z.K.; Gasser T.; Simons E.J.; Breedveld G.J.; Goldwurm S.; Pezzoli G.; Sampaio C.; Barbosa E.; Martignoni E.; Oostra B.A.; Bonifati V.;
Eur. J. Hum. Genet. 14:322-331(2006)
Cited for: VARIANTS PARK8 VAL-1371; CYS-1441 AND SER-2019;

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; 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; PRO-1628; THR-1646; THR-1647; ASP-2081; LEU-2119; ILE-2261 AND THR-2397;

A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.
Zabetian C.P.; Samii A.; Mosley A.D.; Roberts J.W.; Leis B.C.; Yearout D.; Raskind W.H.; Griffith A.;
Neurology 65:741-744(2005)
Cited for: VARIANTS PARK8 CYS-1441; HIS-1441 AND SER-2019;

LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance.
Gaig C.; Ezquerra M.; Marti M.J.; Munoz E.; Valldeoriola F.; Tolosa E.;
Arch. Neurol. 63:377-382(2006)
Cited for: VARIANTS PARK8 CYS-1441; GLY-1441 AND SER-2019;

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.