UniProtKB/Swiss-Prot Q5S007: Variant p.Ile2020Thr

Leucine-rich repeat serine/threonine-protein kinase 2
Gene: LRRK2
Feedback?

Variant information Variant position:

2020 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 Isoleucine (I) to Threonine (T) at position 2020 (I2020T, p.Ile2020Thr). 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 medium size and hydrophobic (I) to medium size and polar (T) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-1 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; significant increase in autophosphorylation of about 40% in comparison to wild-type protein in vitro; shows a progressive reduction in neurite length and branching; shows an increase in activity in phosphorylation of RAB8A and RAB10; 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 rs35870237 [ dbSNP | Ensembl ]

Sequence information Variant position:

2020 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:

VLLFTLYPNAAIIAKIADYG I AQYCCRMGIKTSEGTPGFRA 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                         VLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRA

Mouse                         VLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRA

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	1879 – 2138	Protein kinase
Binding site	2001 – 2001
Binding site	2016 – 2016
Binding site	2017 – 2017
Mutagenesis	2017 – 2017	D -> A. Loss of kinase activity. Decreases proteasomal degradation of MAPT; when associated with A-1906 and N-1994. Loss of phosphorylation of RAB10; when associated with G-1441, C-1699, or S-2019.
Mutagenesis	2019 – 2019	G -> S. 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	2018 – 2025

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 Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
Gloeckner C.J.; Kinkl N.; Schumacher A.; Braun R.J.; O'Neill E.; Meitinger T.; Kolch W.; Prokisch H.; Ueffing M.;
Hum. Mol. Genet. 15:223-232(2006)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT PARK8 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; 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; 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; An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family.
Funayama M.; Hasegawa K.; Ohta E.; Kawashima N.; Komiyama M.; Kowa H.; Tsuji S.; Obata F.;
Ann. Neurol. 57:918-921(2005)
Cited for: VARIANT PARK8 THR-2020; Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease.
Berg D.; Schweitzer K.; Leitner P.; Zimprich A.; Lichtner P.; Belcredi P.; Bruessel T.; Schulte C.; Maass S.; Naegele T.;
Brain 128:3000-3011(2005)
Cited for: VARIANTS PARK8 MET-793; ARG-930; CYS-1096; THR-1228; SER-2019 AND THR-2020; VARIANT LYS-551; 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;

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.