UniProtKB/Swiss-Prot Q5S007: Variant p.Arg1441Gly

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

1441 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 Arginine (R) to Glycine (G) at position 1441 (R1441G, p.Arg1441Gly). 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 glycine (G) 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; shows a progressive reduction in neurite length and branching; shows an increase in activity in phosphorylation of RAB8A and RAB10; decreases phosphorylation-dependent binding to YWHAG; significantly suppresses lysosomal enlargement when overexpressed in LRRK2 knockout cells due to increased phosphorylation of Rab proteins. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs33939927 [ dbSNP | Ensembl ]

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.

Type	Positions	Description
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
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; Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
Chen Z.C.; Zhang W.; Chua L.L.; Chai C.; Li R.; Lin L.; Cao Z.; Angeles D.C.; Stanton L.W.; Peng J.H.; Zhou Z.D.; Lim K.L.; Zeng L.; Tan E.K.;
Sci. Signal. 10:0-0(2017)
Cited for: FUNCTION; CATALYTIC ACTIVITY; COFACTOR; INTERACTION WITH APP; PHOSPHORYLATION AT SER-910 AND SER-935; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441 AND SER-2019; MUTAGENESIS OF ASP-1994; LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis.
Eguchi T.; Kuwahara T.; Sakurai M.; Komori T.; Fujimoto T.; Ito G.; Yoshimura S.I.; Harada A.; Fukuda M.; Koike M.; Iwatsubo T.;
Proc. Natl. Acad. Sci. U.S.A. 115:E9115-E9124(2018)
Cited for: FUNCTION; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; GLY-1441; CYS-1699; SER-2019 AND THR-2020; CHARACTERIZATION OF VARIANT MET-1906; A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.
Dhekne H.S.; Yanatori I.; Gomez R.C.; Tonelli F.; Diez F.; Schuele B.; Steger M.; Alessi D.R.; Pfeffer S.R.;
Elife 7:0-0(2018)
Cited for: FUNCTION; CATALYTIC ACTIVITY; VARIANTS PARK8 GLY-1441 AND SER-2019; 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; 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; 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; LRRK2 R1441G in Spanish patients with Parkinson's disease.
Mata I.F.; Taylor J.P.; Kachergus J.; Hulihan M.; Huerta C.; Lahoz C.; Blazquez M.; Guisasola L.M.; Salvador C.; Ribacoba R.; Martinez C.; Farrer M.; Alvarez V.;
Neurosci. Lett. 382:309-311(2005)
Cited for: VARIANT PARK8 GLY-1441; 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;

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.