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UniProtKB/Swiss-Prot Q5S007: Variant p.Tyr1699Cys

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

Variant position:  1699
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 Tyrosine (Y) to Cysteine (C) at position 1699 (Y1699C, p.Tyr1699Cys).
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 aromatic (Y) to medium size and polar (C)
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

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 no progressive reduction in neurite length and branching; no loss of interaction with SEC16A; shows an increase in activity in phosphorylation of RAB8A and RAB10.
Any additional useful information about the variant.

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



Sequence information

Variant position:  1699
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:   VIELPHCENSEIIIRLYEMP  Y FPMGFWSRLINRLLEISPYM
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                         VIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYM

Mouse                         VIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPFM

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
Mutagenesis 1699 – 1699 Y -> C. 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.


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;

The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
MacLeod D.; Dowman J.; Hammond R.; Leete T.; Inoue K.; Abeliovich A.;
Neuron 52:587-593(2006)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699; SER-2019 AND THR-2020; VARIANT MET-1906;

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;

Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis.
Steger M.; Diez F.; Dhekne H.S.; Lis P.; Nirujogi R.S.; Karayel O.; Tonelli F.; Martinez T.N.; Lorentzen E.; Pfeffer S.R.; Alessi D.R.; Mann M.;
Elife 6:0-0(2017)
Cited for: FUNCTION; CATALYTIC ACTIVITY; COFACTOR; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699 AND SER-2019; MUTAGENESIS OF ASP-2017;

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;

Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.
Paisan-Ruiz C.; Jain S.; Evans E.W.; Gilks W.P.; Simon J.; van der Brug M.; Lopez de Munain A.; Aparicio S.; Gil A.M.; Khan N.L.; Johnson J.; Martinez J.R.; Nicholl D.; Carrera I.M.; Pena A.S.; de Silva R.; Lees A.J.; Marti-Masso J.F.; Perez-Tur J.; Wood N.W.; Singleton A.B.;
Neuron 44:595-600(2004)
Cited for: VARIANTS PARK8 GLY-1441 AND CYS-1699; TISSUE SPECIFICITY;

Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.
Khan N.L.; Jain S.; Lynch J.M.; Pavese N.; Abou-Sleiman P.M.; Holton J.L.; Healy D.G.; Gilks W.P.; Sweeney M.G.; Ganguly M.; Gibbons V.; Gandhi S.; Vaughan J.; Eunson L.H.; Katzenschlager R.; Gayton J.; Lennox G.; Revesz T.; Nicholl D.; Bhatia K.P.; Quinn N.; Brooks D.; Lees A.J.; Davis M.B.; Piccini P.; Singleton A.B.; Wood N.W.;
Brain 128:2786-2796(2005)
Cited for: VARIANTS PARK8 CYS-1699; HIS-1941; SER-2019 AND ILE-2356;

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;

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.