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Protein

Leucine-rich repeat serine/threonine-protein kinase 2

Gene

LRRK2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Phosphorylates PRDX3. Has GTPase activity. May play a role in the phosphorylation of proteins central to Parkinson disease.7 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei1906ATPPROSITE-ProRule annotation1
Active sitei1994Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi1341 – 1348GTPPROSITE-ProRule annotation1 Publication8
Nucleotide bindingi1885 – 1893ATPPROSITE-ProRule annotation9
Nucleotide bindingi2098 – 2121GTPPROSITE-ProRule annotationAdd BLAST24
Nucleotide bindingi2295 – 2298GTPPROSITE-ProRule annotation4

GO - Molecular functioni

  • actin binding Source: ParkinsonsUK-UCL
  • ATP binding Source: UniProtKB-KW
  • beta-catenin destruction complex binding Source: ParkinsonsUK-UCL
  • clathrin binding Source: ParkinsonsUK-UCL
  • co-receptor binding Source: ParkinsonsUK-UCL
  • glycoprotein binding Source: ParkinsonsUK-UCL
  • GTPase activator activity Source: UniProtKB
  • GTPase activity Source: BHF-UCL
  • GTP binding Source: UniProtKB
  • GTP-dependent protein kinase activity Source: UniProtKB
  • identical protein binding Source: IntAct
  • ion channel binding Source: UniProtKB
  • kinase activity Source: UniProtKB
  • MAP kinase kinase activity Source: BHF-UCL
  • microtubule binding Source: ParkinsonsUK-UCL
  • peroxidase inhibitor activity Source: ParkinsonsUK-UCL
  • protein homodimerization activity Source: UniProtKB
  • protein kinase A binding Source: ParkinsonsUK-UCL
  • protein kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
  • receptor signaling complex scaffold activity Source: ParkinsonsUK-UCL
  • Rho GTPase binding Source: BHF-UCL
  • SNARE binding Source: ParkinsonsUK-UCL
  • syntaxin-1 binding Source: ParkinsonsUK-UCL
  • tubulin binding Source: BHF-UCL

GO - Biological processi

  • activation of MAPK activity Source: ParkinsonsUK-UCL
  • activation of MAPKK activity Source: BHF-UCL
  • autophagy Source: UniProtKB-KW
  • calcium-mediated signaling Source: ParkinsonsUK-UCL
  • canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
  • cellular protein localization Source: ParkinsonsUK-UCL
  • cellular response to dopamine Source: ParkinsonsUK-UCL
  • cellular response to manganese ion Source: ParkinsonsUK-UCL
  • cellular response to oxidative stress Source: ParkinsonsUK-UCL
  • cellular response to starvation Source: ParkinsonsUK-UCL
  • determination of adult lifespan Source: BHF-UCL
  • endocytosis Source: ParkinsonsUK-UCL
  • excitatory postsynaptic potential Source: ParkinsonsUK-UCL
  • exploration behavior Source: BHF-UCL
  • Golgi organization Source: ParkinsonsUK-UCL
  • GTP metabolic process Source: BHF-UCL
  • intracellular distribution of mitochondria Source: BHF-UCL
  • intracellular signal transduction Source: ParkinsonsUK-UCL
  • locomotory exploration behavior Source: Ensembl
  • lysosome organization Source: ParkinsonsUK-UCL
  • MAPK cascade Source: UniProtKB
  • mitochondrion localization Source: ParkinsonsUK-UCL
  • mitochondrion organization Source: ParkinsonsUK-UCL
  • negative regulation of autophagosome assembly Source: ParkinsonsUK-UCL
  • negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
  • negative regulation of excitatory postsynaptic potential Source: ParkinsonsUK-UCL
  • negative regulation of GTPase activity Source: MGI
  • negative regulation of hydrogen peroxide-induced cell death Source: ParkinsonsUK-UCL
  • negative regulation of late endosome to lysosome transport Source: ParkinsonsUK-UCL
  • negative regulation of macroautophagy Source: ParkinsonsUK-UCL
  • negative regulation of neuron death Source: ParkinsonsUK-UCL
  • negative regulation of protein binding Source: ParkinsonsUK-UCL
  • negative regulation of protein phosphorylation Source: ParkinsonsUK-UCL
  • negative regulation of protein processing Source: ParkinsonsUK-UCL
  • negative regulation of protein processing involved in protein targeting to mitochondrion Source: ParkinsonsUK-UCL
  • negative regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
  • negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation Source: ParkinsonsUK-UCL
  • neuromuscular junction development Source: BHF-UCL
  • neuron death Source: BHF-UCL
  • neuron projection morphogenesis Source: UniProtKB
  • olfactory bulb development Source: ParkinsonsUK-UCL
  • peptidyl-serine phosphorylation Source: BHF-UCL
  • peptidyl-threonine phosphorylation Source: BHF-UCL
  • phosphorylation Source: ParkinsonsUK-UCL
  • positive regulation of autophagy Source: UniProtKB
  • positive regulation of canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
  • positive regulation of dopamine receptor signaling pathway Source: BHF-UCL
  • positive regulation of MAP kinase activity Source: ParkinsonsUK-UCL
  • positive regulation of programmed cell death Source: UniProtKB
  • positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: BHF-UCL
  • positive regulation of protein autoubiquitination Source: ParkinsonsUK-UCL
  • positive regulation of protein binding Source: ParkinsonsUK-UCL
  • positive regulation of protein phosphorylation Source: ParkinsonsUK-UCL
  • positive regulation of protein ubiquitination Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • protein localization to mitochondrion Source: ParkinsonsUK-UCL
  • protein phosphorylation Source: ParkinsonsUK-UCL
  • reactive oxygen species metabolic process Source: ParkinsonsUK-UCL
  • regulation of autophagy Source: ParkinsonsUK-UCL
  • regulation of branching morphogenesis of a nerve Source: ParkinsonsUK-UCL
  • regulation of CAMKK-AMPK signaling cascade Source: ParkinsonsUK-UCL
  • regulation of canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
  • regulation of dendritic spine morphogenesis Source: ParkinsonsUK-UCL
  • regulation of dopamine receptor signaling pathway Source: ParkinsonsUK-UCL
  • regulation of kidney size Source: BHF-UCL
  • regulation of locomotion Source: BHF-UCL
  • regulation of lysosomal lumen pH Source: ParkinsonsUK-UCL
  • regulation of membrane potential Source: BHF-UCL
  • regulation of mitochondrial depolarization Source: ParkinsonsUK-UCL
  • regulation of mitochondrial fission Source: ParkinsonsUK-UCL
  • regulation of neuroblast proliferation Source: ParkinsonsUK-UCL
  • regulation of neuron death Source: ParkinsonsUK-UCL
  • regulation of neuron maturation Source: ParkinsonsUK-UCL
  • regulation of protein kinase A signaling Source: ParkinsonsUK-UCL
  • regulation of retrograde transport, endosome to Golgi Source: ParkinsonsUK-UCL
  • regulation of synaptic transmission, glutamatergic Source: ParkinsonsUK-UCL
  • regulation of synaptic vesicle exocytosis Source: ParkinsonsUK-UCL
  • regulation of synaptic vesicle transport Source: ParkinsonsUK-UCL
  • response to oxidative stress Source: BHF-UCL
  • small GTPase mediated signal transduction Source: InterPro
  • tangential migration from the subventricular zone to the olfactory bulb Source: ParkinsonsUK-UCL
  • Wnt signalosome assembly Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Molecular functioni

GTPase activation, Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Autophagy, Differentiation

Keywords - Ligandi

ATP-binding, GTP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS11918-MONOMER.
ReactomeiR-HSA-8857538. PTK6 promotes HIF1A stabilization.
SignaLinkiQ5S007.
SIGNORiQ5S007.

Names & Taxonomyi

Protein namesi
Recommended name:
Leucine-rich repeat serine/threonine-protein kinase 2 (EC:2.7.11.1)
Alternative name(s):
Dardarin
Gene namesi
Name:LRRK2
Synonyms:PARK8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:18618. LRRK2.

Subcellular locationi

GO - Cellular componenti

  • amphisome Source: ParkinsonsUK-UCL
  • autolysosome Source: ParkinsonsUK-UCL
  • axon Source: UniProtKB
  • caveola neck Source: ParkinsonsUK-UCL
  • cell junction Source: UniProtKB-KW
  • cytoplasm Source: UniProtKB
  • cytoplasmic side of mitochondrial outer membrane Source: UniProtKB
  • cytoplasmic vesicle Source: UniProtKB
  • cytosol Source: ParkinsonsUK-UCL
  • dendrite Source: UniProtKB
  • dendrite cytoplasm Source: BHF-UCL
  • endoplasmic reticulum Source: UniProtKB
  • endosome Source: UniProtKB
  • extracellular exosome Source: UniProtKB
  • extracellular space Source: UniProtKB
  • Golgi apparatus Source: UniProtKB
  • Golgi-associated vesicle Source: ParkinsonsUK-UCL
  • growth cone Source: ParkinsonsUK-UCL
  • inclusion body Source: ParkinsonsUK-UCL
  • intracellular Source: ParkinsonsUK-UCL
  • intracellular ribonucleoprotein complex Source: Ensembl
  • lysosome Source: UniProtKB
  • microvillus Source: ParkinsonsUK-UCL
  • mitochondrial inner membrane Source: UniProtKB
  • mitochondrial matrix Source: UniProtKB
  • mitochondrial membrane Source: ParkinsonsUK-UCL
  • mitochondrial outer membrane Source: UniProtKB
  • mitochondrion Source: UniProtKB
  • multivesicular body, internal vesicle Source: ParkinsonsUK-UCL
  • neuronal cell body Source: BHF-UCL
  • neuron projection Source: ParkinsonsUK-UCL
  • perikaryon Source: UniProtKB
  • plasma membrane Source: ParkinsonsUK-UCL
  • postsynapse Source: GOC
  • synaptic vesicle membrane Source: UniProtKB-SubCell
  • terminal bouton Source: ParkinsonsUK-UCL
  • trans-Golgi network Source: Ensembl
  • Wnt signalosome Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell projection, Cytoplasm, Cytoplasmic vesicle, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, Membrane, Mitochondrion, Mitochondrion inner membrane, Mitochondrion outer membrane, Synapse

Pathology & Biotechi

Involvement in diseasei

Parkinson disease 8 (PARK8)28 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:607060
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_054741712M → V in PARK8. 1 PublicationCorresponds to variant rs199566791dbSNPEnsembl.1
Natural variantiVAR_024935793R → M in PARK8; unknown pathological significance. 3 PublicationsCorresponds to variant rs35173587dbSNPEnsembl.1
Natural variantiVAR_024936930Q → R in PARK8; unknown pathological significance. 1 PublicationCorresponds to variant rs281865045dbSNPEnsembl.1
Natural variantiVAR_0249381067R → Q in PARK8. 1 PublicationCorresponds to variant rs111341148dbSNPEnsembl.1
Natural variantiVAR_0249391096S → C in PARK8; unknown pathological significance. Corresponds to variant rs76535406dbSNPEnsembl.1
Natural variantiVAR_0249401122I → V in PARK8. 2 PublicationsCorresponds to variant rs34805604dbSNPEnsembl.1
Natural variantiVAR_0249411228S → T in PARK8. 1 PublicationCorresponds to variant rs60185966dbSNPEnsembl.1
Natural variantiVAR_0249431371I → V in PARK8; unknown pathological significance. 2 PublicationsCorresponds to variant rs17466213dbSNPEnsembl.1
Natural variantiVAR_0249461441R → G in PARK8; shows a progressive reduction in neurite length and branching. 5 PublicationsCorresponds to variant rs33939927dbSNPEnsembl.1
Natural variantiVAR_0249471441R → H in PARK8; pathogenicity has yet to be confirmed. 2 PublicationsCorresponds to variant rs34995376dbSNPEnsembl.1
Natural variantiVAR_0249481514R → Q in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. 3 PublicationsCorresponds to variant rs35507033dbSNPEnsembl.1
Natural variantiVAR_0249491542P → S in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. 3 PublicationsCorresponds to variant rs33958906dbSNPEnsembl.1
Natural variantiVAR_0249501598V → E in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. 1 PublicationCorresponds to variant rs721710dbSNPEnsembl.1
Natural variantiVAR_0249541699Y → C in PARK8; shows no progressive reduction in neurite length and branching. 5 PublicationsCorresponds to variant rs35801418dbSNPEnsembl.1
Natural variantiVAR_0547441728R → H in PARK8. 1 PublicationCorresponds to variant rs145364431dbSNPEnsembl.1
Natural variantiVAR_0547451728R → L in PARK8. 1 PublicationCorresponds to variant rs145364431dbSNPEnsembl.1
Natural variantiVAR_0249551869M → T in PARK8; pathogenicity has yet to be confirmed. 2 PublicationsCorresponds to variant rs35602796dbSNPEnsembl.1
Natural variantiVAR_0249561941R → H in PARK8. 1 PublicationCorresponds to variant rs77428810dbSNPEnsembl.1
Natural variantiVAR_0249572012I → T in PARK8; pathogenicity uncertain. 1 PublicationCorresponds to variant rs34015634dbSNPEnsembl.1
Natural variantiVAR_0249582019G → S in PARK8; shows an increase in activity in both autophosphorylation and phosphorylation of a generic substrate; results in increased PRDX3 phosphorylation promoting dysregulation of mitochondrial function and oxidative damage; does not inhibit interaction with RAB29; shows a progressive reduction in neurite length and branching; shows distinctive spheroid-like inclusions within both neuronal processes and at intracellular membranous structures; shows lysosomal swelling and reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows apoptotic mechanism of cell death. 28 PublicationsCorresponds to variant rs34637584dbSNPEnsembl.1
Natural variantiVAR_0249592020I → T 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. 6 PublicationsCorresponds to variant rs35870237dbSNPEnsembl.1
Natural variantiVAR_0547472141T → M in PARK8. 1 PublicationCorresponds to variant rs111691891dbSNPEnsembl.1
Natural variantiVAR_0547482143R → H in PARK8. 1 PublicationCorresponds to variant rs201271001dbSNPEnsembl.1
Natural variantiVAR_0249632356T → I in PARK8. 1 PublicationCorresponds to variant rs113511708dbSNPEnsembl.1
Natural variantiVAR_0547502466L → H in PARK8. 1 PublicationCorresponds to variant rs281865057dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi1343T → G: Decreased kinase activity; when associated with Q-1398. 1 Publication1
Mutagenesisi1398R → Q: Decreased kinase activity; when associated with G-1343. 1 Publication1

Keywords - Diseasei

Disease mutation, Neurodegeneration, Parkinson disease, Parkinsonism

Organism-specific databases

DisGeNETi120892.
MalaCardsiLRRK2.
MIMi168600. phenotype.
607060. phenotype.
OpenTargetsiENSG00000188906.
Orphaneti2828. Young adult-onset Parkinsonism.
PharmGKBiPA134968052.

Chemistry databases

ChEMBLiCHEMBL1075104.
GuidetoPHARMACOLOGYi2059.

Polymorphism and mutation databases

BioMutaiLRRK2.
DMDMi294862450.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862381 – 2527Leucine-rich repeat serine/threonine-protein kinase 2Add BLAST2527

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei935PhosphoserineBy similarity1

Post-translational modificationi

Autophosphorylated.

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ5S007.
PaxDbiQ5S007.
PeptideAtlasiQ5S007.
PRIDEiQ5S007.

PTM databases

iPTMnetiQ5S007.
PhosphoSitePlusiQ5S007.

Expressioni

Tissue specificityi

Expressed in the brain. Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). 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.4 Publications

Gene expression databases

BgeeiENSG00000188906.
CleanExiHS_LRRK2.
ExpressionAtlasiQ5S007. baseline and differential.
GenevisibleiQ5S007. HS.

Organism-specific databases

HPAiCAB037160.
HPA014293.

Interactioni

Subunit structurei

Homodimer. Interacts with PARK2, PRDX3, RAB29, TPCN2 and VPS35.6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself66EBI-5323863,EBI-5323863
AGO2Q9UKV83EBI-5323863,EBI-528269
AKT1P317496EBI-5323863,EBI-296087
ARFGAP1Q8N6T3-26EBI-5323863,EBI-6288865
Arfgap1Q628487EBI-5323863,EBI-4398879From a different organism.
ARHGEF7Q141557EBI-5323863,EBI-717515
BAG2O958162EBI-5323863,EBI-355275
BAG3O958172EBI-5323863,EBI-747185
BAG5Q9UL1512EBI-5323863,EBI-356517
BCL2P10415-12EBI-5323863,EBI-4370304
CDC37Q165437EBI-5323863,EBI-295634
CDC42P609533EBI-5323863,EBI-81752
CHGBP050602EBI-5323863,EBI-712619
Ckmt1P302752EBI-5323863,EBI-773103From a different organism.
CSNK1A1P48729-12EBI-5323863,EBI-10106282
DAPK1P533552EBI-5323863,EBI-358616
DNM1Q051934EBI-5323863,EBI-713135
Dnm1P390533EBI-5323863,EBI-397785From a different organism.
DNM1LO0042911EBI-5323863,EBI-724571
DNM1LO00429-32EBI-5323863,EBI-6896746
DVL1O14640-27EBI-5323863,EBI-6504027
DVL2O146413EBI-5323863,EBI-740850
DVL3Q929974EBI-5323863,EBI-739789
ECHS1P300842EBI-5323863,EBI-719602
FADDQ131584EBI-5323863,EBI-494804
GAKO1497610EBI-5323863,EBI-714707
GSK3BP498417EBI-5323863,EBI-373586
HSPA8P111425EBI-5323863,EBI-351896
LDHBP071952EBI-5323863,EBI-358748
LRP6O755814EBI-5323863,EBI-910915
LRRK1Q38SD25EBI-5323863,EBI-1050422
MAP1BP468215EBI-5323863,EBI-9517186
MAP2K3P467345EBI-5323863,EBI-602462
MAP2K6P525644EBI-5323863,EBI-448135
MAP2K7O147333EBI-5323863,EBI-492605
MAPTP10636-23EBI-5323863,EBI-7796412
MAPTP10636-89EBI-5323863,EBI-366233
MATKP426792EBI-5323863,EBI-751664
MBPP026873EBI-5323863,EBI-908215From a different organism.
Mfn1Q811U43EBI-5323863,EBI-9029118From a different organism.
MFN2O951403EBI-5323863,EBI-3324756
MSNP2603817EBI-5323863,EBI-528768
NEK1Q96PY62EBI-5323863,EBI-373615
NFATC2Q134693EBI-5323863,EBI-716258
NUP133Q8WUM02EBI-5323863,EBI-295695
OPA1O603133EBI-5323863,EBI-1054131
PAK6Q9NQU52EBI-5323863,EBI-1053685
PARK2O602603EBI-5323863,EBI-716346
phoAP006342EBI-5323863,EBI-552958From a different organism.
PPP1CAP621366EBI-5323863,EBI-357253
PRDX3P3004812EBI-5323863,EBI-748336
PRKACAP176126EBI-5323863,EBI-476586
Prkar2bP123693EBI-5323863,EBI-6096160From a different organism.
RAB10P610265EBI-5323863,EBI-726075
RAB12Q6IQ222EBI-5323863,EBI-4289591
RAB1BQ9H0U43EBI-5323863,EBI-1045214
RAB29O149667EBI-5323863,EBI-372165
Rab29Q634813EBI-5323863,EBI-6513837From a different organism.
RAB32Q136376EBI-5323863,EBI-9837586
RAB5BP610209EBI-5323863,EBI-399401
Rab5bP610212EBI-5323863,EBI-8320093From a different organism.
RAB8AP610066EBI-5323863,EBI-722293
RAC1P630005EBI-5323863,EBI-413628
RGS2P412206EBI-5323863,EBI-712388
RPL10AP629062EBI-5323863,EBI-356860
RPL13P263732EBI-5323863,EBI-356849
RPL14P509142EBI-5323863,EBI-356746
RPL23AP627502EBI-5323863,EBI-353254
RPS11P622803EBI-5323863,EBI-1047710
RPS15P628419EBI-5323863,EBI-372635
RPS16P622492EBI-5323863,EBI-352480
RPS2P158802EBI-5323863,EBI-443446
RPS20P608662EBI-5323863,EBI-353105
RPS23P622662EBI-5323863,EBI-353072
RPS27P426772EBI-5323863,EBI-356336
RPS3P233962EBI-5323863,EBI-351193
SEC16AO150276EBI-5323863,EBI-357515
SH3GL2Q999624EBI-5323863,EBI-77938
SLC25A4P122352EBI-5323863,EBI-359074
SLC25A5P051412EBI-5323863,EBI-355133
SLC25A6P122362EBI-5323863,EBI-356254
SNAPINO952955EBI-5323863,EBI-296723
SNCAP378406EBI-5323863,EBI-985879
Spag9Q58A652EBI-5323863,EBI-6530207From a different organism.
TUBBP074374EBI-5323863,EBI-350864
TUBB4AP043504EBI-5323863,EBI-355007
YWHABP319465EBI-5323863,EBI-359815
YWHAEP622586EBI-5323863,EBI-356498
YWHAGP619814EBI-5323863,EBI-359832
YwhagP619836EBI-5323863,EBI-359821From a different organism.
YWHAHQ049173EBI-5323863,EBI-306940
YWHAQP273488EBI-5323863,EBI-359854
YWHAZP631049EBI-5323863,EBI-347088

GO - Molecular functioni

  • actin binding Source: ParkinsonsUK-UCL
  • beta-catenin destruction complex binding Source: ParkinsonsUK-UCL
  • clathrin binding Source: ParkinsonsUK-UCL
  • co-receptor binding Source: ParkinsonsUK-UCL
  • identical protein binding Source: IntAct
  • ion channel binding Source: UniProtKB
  • microtubule binding Source: ParkinsonsUK-UCL
  • protein homodimerization activity Source: UniProtKB
  • protein kinase A binding Source: ParkinsonsUK-UCL
  • receptor signaling complex scaffold activity Source: ParkinsonsUK-UCL
  • Rho GTPase binding Source: BHF-UCL
  • SNARE binding Source: ParkinsonsUK-UCL
  • syntaxin-1 binding Source: ParkinsonsUK-UCL
  • tubulin binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi125700. 151 interactors.
DIPiDIP-29684N.
IntActiQ5S007. 549 interactors.
MINTiMINT-7997594.
STRINGi9606.ENSP00000298910.

Chemistry databases

BindingDBiQ5S007.

Structurei

Secondary structure

12527
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi1336 – 1341Combined sources6
Helixi1347 – 1354Combined sources8
Beta strandi1370 – 1377Combined sources8
Beta strandi1389 – 1395Combined sources7
Helixi1398 – 1402Combined sources5
Helixi1406 – 1411Combined sources6
Beta strandi1412 – 1420Combined sources9
Helixi1421 – 1423Combined sources3
Helixi1425 – 1429Combined sources5
Helixi1431 – 1441Combined sources11
Beta strandi1446 – 1452Combined sources7
Helixi1454 – 1456Combined sources3
Helixi1459 – 1472Combined sources14
Turni1473 – 1475Combined sources3
Beta strandi1481 – 1487Combined sources7
Helixi1495 – 1509Combined sources15

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2ZEJX-ray2.00A/B1333-1516[»]
3D6TX-ray2.43B1335-1505[»]
ProteinModelPortaliQ5S007.
SMRiQ5S007.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ5S007.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati983 – 1004LRR 1Add BLAST22
Repeati1012 – 1033LRR 2Add BLAST22
Repeati1036 – 1057LRR 3Add BLAST22
Repeati1059 – 1080LRR 4Add BLAST22
Repeati1084 – 1105LRR 5Add BLAST22
Repeati1108 – 1129LRR 6Add BLAST22
Repeati1130 – 1150LRR 7Add BLAST21
Repeati1174 – 1196LRR 8Add BLAST23
Repeati1197 – 1218LRR 9Add BLAST22
Repeati1221 – 1241LRR 10Add BLAST21
Repeati1246 – 1267LRR 11Add BLAST22
Repeati1269 – 1291LRR 12Add BLAST23
Domaini1328 – 1511RocPROSITE-ProRule annotationAdd BLAST184
Domaini1879 – 2138Protein kinasePROSITE-ProRule annotationAdd BLAST260
Repeati2139 – 2183WD 1Add BLAST45
Repeati2188 – 2228WD 2Add BLAST41
Repeati2233 – 2276WD 3Add BLAST44
Repeati2281 – 2327WD 4Add BLAST47
Repeati2333 – 2377WD 5Add BLAST45
Repeati2402 – 2438WD 6Add BLAST37
Repeati2443 – 2497WD 7Add BLAST55

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili319 – 348Sequence analysisAdd BLAST30

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi728 – 731Poly-Leu4

Domaini

The seven-bladed WD repeat region is critical for synaptic vesicle trafficking and mediates interaction with multiple vesicle-associated presynaptic proteins.1 Publication
The Roc domain mediates homodimerization and regulates kinase activity.1 Publication

Sequence similaritiesi

Contains 12 LRR (leucine-rich) repeats.Curated
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 Roc domain.PROSITE-ProRule annotation
Contains 7 WD repeats.Curated

Keywords - Domaini

Coiled coil, Leucine-rich repeat, Repeat, WD repeat

Phylogenomic databases

eggNOGiENOG410IRBK. Eukaryota.
KOG0192. Eukaryota.
COG1100. LUCA.
COG4886. LUCA.
GeneTreeiENSGT00530000063477.
HOGENOMiHOG000293315.
HOVERGENiHBG081937.
InParanoidiQ5S007.
KOiK08844.
OMAiFKIRDQP.
OrthoDBiEOG091G003N.
PhylomeDBiQ5S007.
TreeFamiTF313679.

Family and domain databases

Gene3Di1.25.10.10. 2 hits.
1.25.40.20. 1 hit.
2.130.10.10. 1 hit.
3.40.50.300. 1 hit.
3.80.10.10. 2 hits.
InterProiIPR020683. Ankyrin_rpt-contain_dom.
IPR011989. ARM-like.
IPR016024. ARM-type_fold.
IPR032171. COR.
IPR011009. Kinase-like_dom.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR025875. Leu-rich_rpt_4.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR013684. MIRO-like.
IPR027417. P-loop_NTPase.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR020859. ROC_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR005225. Small_GTP-bd_dom.
IPR015943. WD40/YVTN_repeat-like_dom.
IPR017986. WD40_repeat_dom.
[Graphical view]
PfamiPF16095. COR. 1 hit.
PF12799. LRR_4. 1 hit.
PF13855. LRR_8. 1 hit.
PF00069. Pkinase. 1 hit.
PF08477. Roc. 1 hit.
[Graphical view]
SMARTiSM00369. LRR_TYP. 7 hits.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF48371. SSF48371. 2 hits.
SSF50978. SSF50978. 1 hit.
SSF52058. SSF52058. 1 hit.
SSF52540. SSF52540. 1 hit.
SSF56112. SSF56112. 1 hit.
TIGRFAMsiTIGR00231. small_GTP. 1 hit.
PROSITEiPS51450. LRR. 11 hits.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS51424. ROC. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q5S007-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MASGSCQGCE EDEETLKKLI VRLNNVQEGK QIETLVQILE DLLVFTYSER
60 70 80 90 100
ASKLFQGKNI HVPLLIVLDS YMRVASVQQV GWSLLCKLIE VCPGTMQSLM
110 120 130 140 150
GPQDVGNDWE VLGVHQLILK MLTVHNASVN LSVIGLKTLD LLLTSGKITL
160 170 180 190 200
LILDEESDIF MLIFDAMHSF PANDEVQKLG CKALHVLFER VSEEQLTEFV
210 220 230 240 250
ENKDYMILLS ALTNFKDEEE IVLHVLHCLH SLAIPCNNVE VLMSGNVRCY
260 270 280 290 300
NIVVEAMKAF PMSERIQEVS CCLLHRLTLG NFFNILVLNE VHEFVVKAVQ
310 320 330 340 350
QYPENAALQI SALSCLALLT ETIFLNQDLE EKNENQENDD EGEEDKLFWL
360 370 380 390 400
EACYKALTWH RKNKHVQEAA CWALNNLLMY QNSLHEKIGD EDGHFPAHRE
410 420 430 440 450
VMLSMLMHSS SKEVFQASAN ALSTLLEQNV NFRKILLSKG IHLNVLELMQ
460 470 480 490 500
KHIHSPEVAE SGCKMLNHLF EGSNTSLDIM AAVVPKILTV MKRHETSLPV
510 520 530 540 550
QLEALRAILH FIVPGMPEES REDTEFHHKL NMVKKQCFKN DIHKLVLAAL
560 570 580 590 600
NRFIGNPGIQ KCGLKVISSI VHFPDALEML SLEGAMDSVL HTLQMYPDDQ
610 620 630 640 650
EIQCLGLSLI GYLITKKNVF IGTGHLLAKI LVSSLYRFKD VAEIQTKGFQ
660 670 680 690 700
TILAILKLSA SFSKLLVHHS FDLVIFHQMS SNIMEQKDQQ FLNLCCKCFA
710 720 730 740 750
KVAMDDYLKN VMLERACDQN NSIMVECLLL LGADANQAKE GSSLICQVCE
760 770 780 790 800
KESSPKLVEL LLNSGSREQD VRKALTISIG KGDSQIISLL LRRLALDVAN
810 820 830 840 850
NSICLGGFCI GKVEPSWLGP LFPDKTSNLR KQTNIASTLA RMVIRYQMKS
860 870 880 890 900
AVEEGTASGS DGNFSEDVLS KFDEWTFIPD SSMDSVFAQS DDLDSEGSEG
910 920 930 940 950
SFLVKKKSNS ISVGEFYRDA VLQRCSPNLQ RHSNSLGPIF DHEDLLKRKR
960 970 980 990 1000
KILSSDDSLR SSKLQSHMRH SDSISSLASE REYITSLDLS ANELRDIDAL
1010 1020 1030 1040 1050
SQKCCISVHL EHLEKLELHQ NALTSFPQQL CETLKSLTHL DLHSNKFTSF
1060 1070 1080 1090 1100
PSYLLKMSCI ANLDVSRNDI GPSVVLDPTV KCPTLKQFNL SYNQLSFVPE
1110 1120 1130 1140 1150
NLTDVVEKLE QLILEGNKIS GICSPLRLKE LKILNLSKNH ISSLSENFLE
1160 1170 1180 1190 1200
ACPKVESFSA RMNFLAAMPF LPPSMTILKL SQNKFSCIPE AILNLPHLRS
1210 1220 1230 1240 1250
LDMSSNDIQY LPGPAHWKSL NLRELLFSHN QISILDLSEK AYLWSRVEKL
1260 1270 1280 1290 1300
HLSHNKLKEI PPEIGCLENL TSLDVSYNLE LRSFPNEMGK LSKIWDLPLD
1310 1320 1330 1340 1350
ELHLNFDFKH IGCKAKDIIR FLQQRLKKAV PYNRMKLMIV GNTGSGKTTL
1360 1370 1380 1390 1400
LQQLMKTKKS DLGMQSATVG IDVKDWPIQI RDKRKRDLVL NVWDFAGREE
1410 1420 1430 1440 1450
FYSTHPHFMT QRALYLAVYD LSKGQAEVDA MKPWLFNIKA RASSSPVILV
1460 1470 1480 1490 1500
GTHLDVSDEK QRKACMSKIT KELLNKRGFP AIRDYHFVNA TEESDALAKL
1510 1520 1530 1540 1550
RKTIINESLN FKIRDQLVVG QLIPDCYVEL EKIILSERKN VPIEFPVIDR
1560 1570 1580 1590 1600
KRLLQLVREN QLQLDENELP HAVHFLNESG VLLHFQDPAL QLSDLYFVEP
1610 1620 1630 1640 1650
KWLCKIMAQI LTVKVEGCPK HPKGIISRRD VEKFLSKKRK FPKNYMSQYF
1660 1670 1680 1690 1700
KLLEKFQIAL PIGEEYLLVP SSLSDHRPVI ELPHCENSEI IIRLYEMPYF
1710 1720 1730 1740 1750
PMGFWSRLIN RLLEISPYML SGRERALRPN RMYWRQGIYL NWSPEAYCLV
1760 1770 1780 1790 1800
GSEVLDNHPE SFLKITVPSC RKGCILLGQV VDHIDSLMEE WFPGLLEIDI
1810 1820 1830 1840 1850
CGEGETLLKK WALYSFNDGE EHQKILLDDL MKKAEEGDLL VNPDQPRLTI
1860 1870 1880 1890 1900
PISQIAPDLI LADLPRNIML NNDELEFEQA PEFLLGDGSF GSVYRAAYEG
1910 1920 1930 1940 1950
EEVAVKIFNK HTSLRLLRQE LVVLCHLHHP SLISLLAAGI RPRMLVMELA
1960 1970 1980 1990 2000
SKGSLDRLLQ QDKASLTRTL QHRIALHVAD GLRYLHSAMI IYRDLKPHNV
2010 2020 2030 2040 2050
LLFTLYPNAA IIAKIADYGI AQYCCRMGIK TSEGTPGFRA PEVARGNVIY
2060 2070 2080 2090 2100
NQQADVYSFG LLLYDILTTG GRIVEGLKFP NEFDELEIQG KLPDPVKEYG
2110 2120 2130 2140 2150
CAPWPMVEKL IKQCLKENPQ ERPTSAQVFD ILNSAELVCL TRRILLPKNV
2160 2170 2180 2190 2200
IVECMVATHH NSRNASIWLG CGHTDRGQLS FLDLNTEGYT SEEVADSRIL
2210 2220 2230 2240 2250
CLALVHLPVE KESWIVSGTQ SGTLLVINTE DGKKRHTLEK MTDSVTCLYC
2260 2270 2280 2290 2300
NSFSKQSKQK NFLLVGTADG KLAIFEDKTV KLKGAAPLKI LNIGNVSTPL
2310 2320 2330 2340 2350
MCLSESTNST ERNVMWGGCG TKIFSFSNDF TIQKLIETRT SQLFSYAAFS
2360 2370 2380 2390 2400
DSNIITVVVD TALYIAKQNS PVVEVWDKKT EKLCGLIDCV HFLREVMVKE
2410 2420 2430 2440 2450
NKESKHKMSY SGRVKTLCLQ KNTALWIGTG GGHILLLDLS TRRLIRVIYN
2460 2470 2480 2490 2500
FCNSVRVMMT AQLGSLKNVM LVLGYNRKNT EGTQKQKEIQ SCLTVWDINL
2510 2520
PHEVQNLEKH IEVRKELAEK MRRTSVE
Length:2,527
Mass (Da):286,103
Last modified:April 20, 2010 - v2
Checksum:i26142A0CECBBC3F4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti212L → S in AAV63975 (PubMed:15541309).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02493150R → H.Corresponds to variant rs2256408dbSNPEnsembl.1
Natural variantiVAR_024932119L → P.2 PublicationsCorresponds to variant rs33995463dbSNPEnsembl.1
Natural variantiVAR_054740228C → S.1 PublicationCorresponds to variant rs56108242dbSNPEnsembl.1
Natural variantiVAR_033903419A → V.1 PublicationCorresponds to variant rs34594498dbSNPEnsembl.1
Natural variantiVAR_024933551N → K.4 PublicationsCorresponds to variant rs7308720dbSNPEnsembl.1
Natural variantiVAR_054741712M → V in PARK8. 1 PublicationCorresponds to variant rs199566791dbSNPEnsembl.1
Natural variantiVAR_054742716A → V.1 PublicationCorresponds to variant rs281865043dbSNPEnsembl.1
Natural variantiVAR_024934723I → V.3 PublicationsCorresponds to variant rs10878307dbSNPEnsembl.1
Natural variantiVAR_033904755P → L.Corresponds to variant rs34410987dbSNPEnsembl.1
Natural variantiVAR_024935793R → M in PARK8; unknown pathological significance. 3 PublicationsCorresponds to variant rs35173587dbSNPEnsembl.1
Natural variantiVAR_054743871K → E.1 PublicationCorresponds to variant rs281865044dbSNPEnsembl.1
Natural variantiVAR_024936930Q → R in PARK8; unknown pathological significance. 1 PublicationCorresponds to variant rs281865045dbSNPEnsembl.1
Natural variantiVAR_024937944D → Y.Corresponds to variant rs17519916dbSNPEnsembl.1
Natural variantiVAR_0249381067R → Q in PARK8. 1 PublicationCorresponds to variant rs111341148dbSNPEnsembl.1
Natural variantiVAR_0249391096S → C in PARK8; unknown pathological significance. Corresponds to variant rs76535406dbSNPEnsembl.1
Natural variantiVAR_0249401122I → V in PARK8. 2 PublicationsCorresponds to variant rs34805604dbSNPEnsembl.1
Natural variantiVAR_0249411228S → T in PARK8. 1 PublicationCorresponds to variant rs60185966dbSNPEnsembl.1
Natural variantiVAR_0249421262P → A.1 PublicationCorresponds to variant rs4640000dbSNPEnsembl.1
Natural variantiVAR_0647281359K → I Found in a renal cell carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_0249431371I → V in PARK8; unknown pathological significance. 2 PublicationsCorresponds to variant rs17466213dbSNPEnsembl.1
Natural variantiVAR_0470221375D → E.Corresponds to variant rs28365226dbSNPEnsembl.1
Natural variantiVAR_0249441398R → H.4 PublicationsCorresponds to variant rs7133914dbSNPEnsembl.1
Natural variantiVAR_0249451441R → C in PARK; shows an increase in activity in both autophosphorylation and phosphorylation of a generic substrate. 6 PublicationsCorresponds to variant rs33939927dbSNPEnsembl.1
Natural variantiVAR_0249461441R → G in PARK8; shows a progressive reduction in neurite length and branching. 5 PublicationsCorresponds to variant rs33939927dbSNPEnsembl.1
Natural variantiVAR_0249471441R → H in PARK8; pathogenicity has yet to be confirmed. 2 PublicationsCorresponds to variant rs34995376dbSNPEnsembl.1
Natural variantiVAR_0249481514R → Q in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. 3 PublicationsCorresponds to variant rs35507033dbSNPEnsembl.1
Natural variantiVAR_0249491542P → S in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. 3 PublicationsCorresponds to variant rs33958906dbSNPEnsembl.1
Natural variantiVAR_0406781550R → Q in an ovarian mucinous carcinoma sample; somatic mutation. 1 PublicationCorresponds to variant rs200212150dbSNPEnsembl.1
Natural variantiVAR_0249501598V → E in PARK8; pathogenicity has yet to be confirmed; might have an effect on protein structure. 1 PublicationCorresponds to variant rs721710dbSNPEnsembl.1
Natural variantiVAR_0249511628R → P May be associated with Parkinson disease in some populations. 3 PublicationsCorresponds to variant rs33949390dbSNPEnsembl.1
Natural variantiVAR_0249521646M → T.2 PublicationsCorresponds to variant rs35303786dbSNPEnsembl.1
Natural variantiVAR_0249531647S → T.2 PublicationsCorresponds to variant rs11564148dbSNPEnsembl.1
Natural variantiVAR_0249541699Y → C in PARK8; shows no progressive reduction in neurite length and branching. 5 PublicationsCorresponds to variant rs35801418dbSNPEnsembl.1
Natural variantiVAR_0406791723R → P in an ovarian serous carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_0547441728R → H in PARK8. 1 PublicationCorresponds to variant rs145364431dbSNPEnsembl.1
Natural variantiVAR_0547451728R → L in PARK8. 1 PublicationCorresponds to variant rs145364431dbSNPEnsembl.1
Natural variantiVAR_0249551869M → T in PARK8; pathogenicity has yet to be confirmed. 2 PublicationsCorresponds to variant rs35602796dbSNPEnsembl.1
Natural variantiVAR_0547461870L → F.1 PublicationCorresponds to variant rs281865053dbSNPEnsembl.1
Natural variantiVAR_0711011906K → M Does not inhibit interaction with RAB29; shows a progressive increase in neurite length and branching. 2 Publications1
Natural variantiVAR_0249561941R → H in PARK8. 1 PublicationCorresponds to variant rs77428810dbSNPEnsembl.1
Natural variantiVAR_0249572012I → T in PARK8; pathogenicity uncertain. 1 PublicationCorresponds to variant rs34015634dbSNPEnsembl.1
Natural variantiVAR_0249582019G → S in PARK8; shows an increase in activity in both autophosphorylation and phosphorylation of a generic substrate; results in increased PRDX3 phosphorylation promoting dysregulation of mitochondrial function and oxidative damage; does not inhibit interaction with RAB29; shows a progressive reduction in neurite length and branching; shows distinctive spheroid-like inclusions within both neuronal processes and at intracellular membranous structures; shows lysosomal swelling and reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows apoptotic mechanism of cell death. 28 PublicationsCorresponds to variant rs34637584dbSNPEnsembl.1
Natural variantiVAR_0249592020I → T 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. 6 PublicationsCorresponds to variant rs35870237dbSNPEnsembl.1
Natural variantiVAR_0249602081N → D.2 PublicationsCorresponds to variant rs33995883dbSNPEnsembl.1
Natural variantiVAR_0249612119P → L.1 PublicationCorresponds to variant rs12423862dbSNPEnsembl.1
Natural variantiVAR_0547472141T → M in PARK8. 1 PublicationCorresponds to variant rs111691891dbSNPEnsembl.1
Natural variantiVAR_0547482143R → H in PARK8. 1 PublicationCorresponds to variant rs201271001dbSNPEnsembl.1
Natural variantiVAR_0249622261N → I.1 PublicationCorresponds to variant rs12581902dbSNPEnsembl.1
Natural variantiVAR_0249632356T → I in PARK8. 1 PublicationCorresponds to variant rs113511708dbSNPEnsembl.1
Natural variantiVAR_0249642385G → R Associated with Parkinson disease; under conditions of oxidative stress the variant protein is more toxic and is associated with a higher rate of apoptosis; reduced binding to synaptic vesicles. 3 Publications