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Reviewed, UniProtKB/Swiss-Prot Q5S007 (LRRK2_HUMAN)

Last modified November 25, 2008. Version 45. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    Leucine-rich repeat serine/threonine-protein kinase 2
    EC=2.7.11.1
Alternative name(s):
    Dardarin
Gene names
Name: LRRK2
Synonyms: PARK8
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length2527 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Probable protein kinase whose role is not yet known. May play a role in the phosphorylation of proteins central to Parkinson disease. May also have GTPase activity.

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Subunit structure

Interacts with PARK2.

Subcellular location

Cytoplasm. Membrane; Peripheral membrane protein. Note= Localized in the cytoplasm and associated with cellular membrane structures. Associates with the mitochondrial outer membrane.

Tissue specificity

Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas.

Involvement in disease

Defects in LRRK2 are the cause of Parkinson disease 8 (PARK8) [MIM:607060, 168600]. Parkinson disease (PD) is a complex, multifactorial disorder that typically manifests after the age of 50 years, although early-onset cases (before 50 years) are known. PD generally arises as a sporadic condition but is occasionally inherited as a simple mendelian trait. Although sporadic and familial PD are very similar, inherited forms of the disease usually begin at earlier ages and are associated with atypical clinical features. PD is characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. PARK8 is an autosomal-dominant late-onset parkinsonism, characterized by onset from 50 to 65 years, with slow progression and relatively benign course.

Sequence similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Contains 16 LRR (leucine-rich) repeats.

Contains 1 Miro domain.

Contains 1 protein kinase domain.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 25272527Leucine-rich repeat serine/threonine-protein kinase 2
PRO_0000086238

Regions

Repeat226 – 24924LRR 1
Repeat791 – 81525LRR 2
Repeat981 – 100424LRR 3
Repeat1010 – 103324LRR 4
Repeat1035 – 105723LRR 5
Repeat1059 – 108123LRR 6
Repeat1082 – 110524LRR 7
Repeat1107 – 112721LRR 8
Repeat1128 – 115124LRR 9
Repeat1172 – 119423LRR 10
Repeat1195 – 121925LRR 11
Repeat1221 – 124323LRR 12
Repeat1244 – 126825LRR 13
Repeat1270 – 129122LRR 14
Domain1335 – 1455121Miro
Repeat1556 – 157924LRR 15
Repeat1861 – 188727LRR 16
Domain1879 – 2138260Protein kinase
Nucleotide binding1341 – 13488GTP Potential
Nucleotide binding1885 – 18939ATP By similarity
Nucleotide binding2098 – 212124GTP Potential
Nucleotide binding2295 – 22984GTP Potential
Coiled coil319 – 34830 Potential
Compositional bias728 – 7314Poly-Leu

Sites

Active site19941Proton acceptor By similarity
Binding site19061ATP By similarity

Natural variations

Natural variant501H → R: dbSNP rs2256408.
VAR_024931
Natural variant1191L → P: dbSNP rs33995463.
VAR_024932
Natural variant4191A → V: dbSNP rs34594498.
VAR_033903
Natural variant5511N → K: dbSNP rs7308720.
VAR_024933
Natural variant7231I → V: dbSNP rs10878307.
VAR_024934
Natural variant7551P → L: dbSNP rs34410987.
VAR_033904
Natural variant7931R → M in PARK8 and PD; idiopathic and late onset sporadic; could be a polymorphism. dbSNP rs35173587.
VAR_024935
Natural variant9301Q → R in PARK8; could be a poymorphism.
VAR_024936
Natural variant9441D → Y: dbSNP rs17519916.
VAR_024937
Natural variant10671R → Q in PD; familial nondominant.
VAR_024938
Natural variant10961S → C in PARK8; could be a polymorphism.
VAR_024939
Natural variant11221I → V in PARK8. dbSNP rs34805604.
VAR_024940
Natural variant12281S → T in PARK8.
VAR_024941
Natural variant12621P → A: dbSNP rs4640000.
VAR_024942
Natural variant13711I → V in PARK8 and PD; could be a polymorphism. dbSNP rs17466213.
VAR_024943
Natural variant13751D → E: dbSNP rs28365226.
VAR_047022
Natural variant13981R → H: dbSNP rs7133914.
VAR_024944
Natural variant14411R → C in PARK8 and PD; autosomal dominant inheritance; show an increase in activity in both autophosphorylation and phosphorylation of a generic substrate. dbSNP rs34995376.
VAR_024945
Natural variant14411R → G in PARK8 and PD; sporadic late-onset patients.
VAR_024946
Natural variant14411R → H in PARK8 and PD; sporadic; pathogenicity has yet to be confirmed.
VAR_024947
Natural variant15141R → Q in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. dbSNP rs35507033.
VAR_024948
Natural variant15421P → S in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. dbSNP rs33958906.
VAR_024949
Natural variant15501R → Q in an ovarian mucinous carcinoma sample; somatic mutation.
VAR_040678
Natural variant15981V → E in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. dbSNP rs721710.
VAR_024950
Natural variant16281R → P: dbSNP rs33949390.
VAR_024951
Natural variant16461M → T
VAR_024952
Natural variant16471S → T: dbSNP rs11564148.
VAR_024953
Natural variant16991Y → C in PARK8. dbSNP rs35801418.
VAR_024954
Natural variant17231R → P in an ovarian serous carcinoma sample; somatic mutation.
VAR_040679
Natural variant18691M → T in PARK8 and PD; pathogenicity has yet to be confirmed.
VAR_024955
Natural variant19411R → H in PARK8.
VAR_024956
Natural variant20121I → T in PARK8; pathogenicity uncertain.
VAR_024957
Natural variant20191G → S in PARK8 and PD; idiopathic or sporadic; the most common genetic determinant of PD identified so far; show an increase in activity in both autophosphorylation and phosphorylation of a generic substrate.
VAR_024958
Natural variant20201I → T in PARK8; significant increase in autophosphorylation of about 40% in comparison to wild-type protein in vitro.
VAR_024959
Natural variant20811N → D
VAR_024960
Natural variant21191P → L: dbSNP rs12423862.
VAR_024961
Natural variant22611N → I: dbSNP rs12581902.
VAR_024962
Natural variant23561T → I in PARK8.
VAR_024963
Natural variant23851G → R in PARK8; pathogenicity has yet to be confirmed.
VAR_024964
Natural variant23971M → T: dbSNP rs3761863.
VAR_024965

Experimental info

Sequence conflict1260 – 127112IPPEI…LENLT → VRRLLPLKKYTL Ref.2

Secondary structure

1 .............................. 2527
Helix Strand Turn

Details...