Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

E3 ubiquitin-protein ligase parkin

Gene

PARK2

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

Functioni

Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2 (PubMed:10973942, PubMed:10888878, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:16135753, PubMed:21376232, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11590439, PubMed:11431533, PubMed:19229105, PubMed:11590439, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (PubMed:25621951). Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in the regulation of neuron death (PubMed:21376232). Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.28 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.1 Publication

Enzyme regulationi

In the autoinhibited state the side chain of Phe-463 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-431, whereas the REP repressor element binds RING-1 and blocks its E2-binding site (PubMed:23727886, PubMed:23770887). Activation of PARK2 requires 2 steps: (1) phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated ubiquitin, leading to unlock repression of the catalytic Cys-431 by the RING-0 region via an allosteric mechanism and converting PARK2 to its fully-active form (PubMed:24660806, PubMed:24784582, PubMed:25527291). According to another report, phosphorylation at Ser-65 by PINK1 is not essential for activation and only binding to phosphorylated ubiquitin is essential to unlock repression (PubMed:24751536).6 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei431By similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri141 – 225RING-type 0; atypicalAdd BLAST85
Zinc fingeri238 – 293RING-type 1; atypicalAdd BLAST56
Zinc fingeri313 – 377IBR-typeAdd BLAST65
Zinc fingeri418 – 449RING-type 2Add BLAST32

GO - Molecular functioni

  • actin binding Source: ParkinsonsUK-UCL
  • beta-catenin binding Source: ParkinsonsUK-UCL
  • chaperone binding Source: BHF-UCL
  • cullin family protein binding Source: ParkinsonsUK-UCL
  • enzyme binding Source: ParkinsonsUK-UCL
  • F-box domain binding Source: ParkinsonsUK-UCL
  • G-protein coupled receptor binding Source: ParkinsonsUK-UCL
  • heat shock protein binding Source: ParkinsonsUK-UCL
  • histone deacetylase binding Source: ParkinsonsUK-UCL
  • Hsp70 protein binding Source: ParkinsonsUK-UCL
  • identical protein binding Source: IntAct
  • kinase binding Source: UniProtKB
  • PDZ domain binding Source: BHF-UCL
  • phospholipase binding Source: ParkinsonsUK-UCL
  • protein kinase binding Source: UniProtKB
  • SH3 domain binding Source: ParkinsonsUK-UCL
  • transcription factor activity, sequence-specific DNA binding Source: ParkinsonsUK-UCL
  • transcription regulatory region sequence-specific DNA binding Source: ParkinsonsUK-UCL
  • tubulin binding Source: ParkinsonsUK-UCL
  • ubiquitin binding Source: UniProtKB
  • ubiquitin conjugating enzyme binding Source: ParkinsonsUK-UCL
  • ubiquitin protein ligase activity Source: UniProtKB
  • ubiquitin protein ligase activity involved in ERAD pathway Source: ParkinsonsUK-UCL
  • ubiquitin protein ligase binding Source: UniProtKB
  • ubiquitin-protein transferase activity Source: UniProtKB
  • ubiquitin-specific protease binding Source: ParkinsonsUK-UCL
  • zinc ion binding Source: ParkinsonsUK-UCL

GO - Biological processi

  • adult locomotory behavior Source: ParkinsonsUK-UCL
  • aggresome assembly Source: BHF-UCL
  • cellular protein catabolic process Source: ParkinsonsUK-UCL
  • cellular protein metabolic process Source: Reactome
  • cellular response to dopamine Source: ParkinsonsUK-UCL
  • cellular response to manganese ion Source: ParkinsonsUK-UCL
  • cellular response to toxic substance Source: ParkinsonsUK-UCL
  • cellular response to unfolded protein Source: ParkinsonsUK-UCL
  • central nervous system development Source: ProtInc
  • dopamine metabolic process Source: ParkinsonsUK-UCL
  • dopamine uptake involved in synaptic transmission Source: Ensembl
  • ERAD pathway Source: ParkinsonsUK-UCL
  • free ubiquitin chain polymerization Source: ParkinsonsUK-UCL
  • learning Source: Ensembl
  • macroautophagy Source: Reactome
  • mitochondrial fission Source: ParkinsonsUK-UCL
  • mitochondrion organization Source: ParkinsonsUK-UCL
  • mitochondrion to lysosome transport Source: ParkinsonsUK-UCL
  • mitophagy Source: UniProtKB
  • mitophagy in response to mitochondrial depolarization Source: ParkinsonsUK-UCL
  • negative regulation by host of viral genome replication Source: AgBase
  • negative regulation of actin filament bundle assembly Source: BHF-UCL
  • negative regulation of canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
  • negative regulation of cell death Source: BHF-UCL
  • negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
  • negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway Source: Ensembl
  • negative regulation of exosomal secretion Source: ParkinsonsUK-UCL
  • negative regulation of gene expression Source: ParkinsonsUK-UCL
  • negative regulation of glucokinase activity Source: MGI
  • negative regulation of insulin secretion Source: MGI
  • negative regulation of intralumenal vesicle formation Source: ParkinsonsUK-UCL
  • negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator Source: ParkinsonsUK-UCL
  • negative regulation of JNK cascade Source: ParkinsonsUK-UCL
  • negative regulation of mitochondrial fusion Source: ParkinsonsUK-UCL
  • negative regulation of neuron apoptotic process Source: ParkinsonsUK-UCL
  • negative regulation of neuron death Source: ParkinsonsUK-UCL
  • negative regulation of oxidative stress-induced cell death Source: ParkinsonsUK-UCL
  • negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
  • negative regulation of primary amine oxidase activity Source: ParkinsonsUK-UCL
  • negative regulation of protein phosphorylation Source: BHF-UCL
  • negative regulation of reactive oxygen species metabolic process Source: ParkinsonsUK-UCL
  • negative regulation of release of cytochrome c from mitochondria Source: BHF-UCL
  • negative regulation of spontaneous neurotransmitter secretion Source: ParkinsonsUK-UCL
  • negative regulation of transcription from RNA polymerase II promoter Source: ParkinsonsUK-UCL
  • neuron cellular homeostasis Source: ParkinsonsUK-UCL
  • norepinephrine metabolic process Source: Ensembl
  • parkin-mediated mitophagy in response to mitochondrial depolarization Source: ParkinsonsUK-UCL
  • positive regulation of dendrite extension Source: Ensembl
  • positive regulation of DNA binding Source: ParkinsonsUK-UCL
  • positive regulation of gene expression Source: ParkinsonsUK-UCL
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: ParkinsonsUK-UCL
  • positive regulation of mitochondrial fission Source: ParkinsonsUK-UCL
  • positive regulation of mitochondrial fusion Source: ParkinsonsUK-UCL
  • positive regulation of neurotransmitter uptake Source: ParkinsonsUK-UCL
  • positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway Source: Ensembl
  • positive regulation of proteasomal protein catabolic process Source: ParkinsonsUK-UCL
  • positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
  • positive regulation of protein binding Source: ParkinsonsUK-UCL
  • positive regulation of protein catabolic process Source: ParkinsonsUK-UCL
  • positive regulation of protein linear polyubiquitination Source: ParkinsonsUK-UCL
  • positive regulation of protein localization to membrane Source: ParkinsonsUK-UCL
  • positive regulation of retrograde transport, endosome to Golgi Source: ParkinsonsUK-UCL
  • positive regulation of transcription from RNA polymerase II promoter Source: ParkinsonsUK-UCL
  • positive regulation of tumor necrosis factor-mediated signaling pathway Source: ParkinsonsUK-UCL
  • proteasomal protein catabolic process Source: ParkinsonsUK-UCL
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
  • protein autoubiquitination Source: UniProtKB
  • protein destabilization Source: ParkinsonsUK-UCL
  • protein K11-linked ubiquitination Source: UniProtKB
  • protein K27-linked ubiquitination Source: ParkinsonsUK-UCL
  • protein K29-linked ubiquitination Source: ParkinsonsUK-UCL
  • protein K48-linked ubiquitination Source: UniProtKB
  • protein K63-linked ubiquitination Source: UniProtKB
  • protein K6-linked ubiquitination Source: UniProtKB
  • protein localization to mitochondrion Source: Ensembl
  • protein monoubiquitination Source: UniProtKB
  • protein polyubiquitination Source: UniProtKB
  • protein stabilization Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: UniProtKB
  • regulation of autophagy Source: UniProtKB
  • regulation of canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
  • regulation of cellular response to oxidative stress Source: ParkinsonsUK-UCL
  • regulation of dopamine metabolic process Source: ParkinsonsUK-UCL
  • regulation of dopamine secretion Source: ParkinsonsUK-UCL
  • regulation of glucose metabolic process Source: ParkinsonsUK-UCL
  • regulation of lipid transport Source: ParkinsonsUK-UCL
  • regulation of mitochondrial membrane potential Source: Ensembl
  • regulation of mitochondrion organization Source: ParkinsonsUK-UCL
  • regulation of protein stability Source: ParkinsonsUK-UCL
  • regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
  • regulation of protein ubiquitination Source: ParkinsonsUK-UCL
  • regulation of reactive oxygen species metabolic process Source: UniProtKB
  • regulation of synaptic vesicle transport Source: ParkinsonsUK-UCL
  • response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • response to oxidative stress Source: ParkinsonsUK-UCL
  • startle response Source: Ensembl
  • synaptic transmission, glutamatergic Source: Ensembl
  • transcription, DNA-templated Source: UniProtKB-KW
  • zinc ion homeostasis Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Molecular functioni

Transferase

Keywords - Biological processi

Autophagy, Transcription, Transcription regulation, Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BRENDAi2.3.2.B10. 2681.
ReactomeiR-HSA-5205685. Pink/Parkin Mediated Mitophagy.
R-HSA-5689877. Josephin domain DUBs.
R-HSA-977225. Amyloid fiber formation.
R-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.
SignaLinkiO60260.
SIGNORiO60260.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase parkin (EC:2.3.2.-1 Publication)
Short name:
Parkin
Alternative name(s):
Parkinson juvenile disease protein 2
Short name:
Parkinson disease protein 2
Gene namesi
Name:PARK2
Synonyms:PRKN
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:8607. PARK2.

Subcellular locationi

GO - Cellular componenti

  • aggresome Source: BHF-UCL
  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • endoplasmic reticulum Source: ParkinsonsUK-UCL
  • Golgi apparatus Source: UniProtKB
  • Lewy body Source: ParkinsonsUK-UCL
  • mitochondrion Source: UniProtKB
  • neuron projection Source: ParkinsonsUK-UCL
  • nucleus Source: ParkinsonsUK-UCL
  • Parkin-FBXW7-Cul1 ubiquitin ligase complex Source: ParkinsonsUK-UCL
  • perinuclear region of cytoplasm Source: UniProtKB
  • presynapse Source: GOC
  • protein complex Source: Ensembl
  • ubiquitin ligase complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Parkinson disease (PARK)2 Publications
Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996 and PubMed:12629236).
Disease descriptionA complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease 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. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.
See also OMIM:168600
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01973315V → M in PARK2. 1 PublicationCorresponds to variant rs532703934dbSNPEnsembl.1
Natural variantiVAR_01973433R → Q in PARK2. 1 PublicationCorresponds to variant rs147757966dbSNPEnsembl.1
Natural variantiVAR_01973537P → L in PARK2. 1 PublicationCorresponds to variant rs148990138dbSNPEnsembl.1
Natural variantiVAR_01973642R → P in PARK2; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding; Decreases ubiquitination and degradation. 5 PublicationsCorresponds to variant rs368134308dbSNPEnsembl.1
Natural variantiVAR_01973746A → P in PARK2. 1 Publication1
Natural variantiVAR_07007856V → E in PARK2. 1 PublicationCorresponds to variant rs137853059dbSNPEnsembl.1
Natural variantiVAR_01973882A → E in PARK2. 3 PublicationsCorresponds to variant rs55774500dbSNPEnsembl.1
Natural variantiVAR_01973992A → V in PARK2. Corresponds to variant rs566229879dbSNPEnsembl.1
Natural variantiVAR_019741161K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 5 PublicationsCorresponds to variant rs137853057dbSNPEnsembl.1
Natural variantiVAR_054107192M → L in PARK2; unknown pathological significance. 1 PublicationCorresponds to variant rs9456735dbSNPEnsembl.1
Natural variantiVAR_019743192M → V in PARK2; unknown pathological significance. 1 PublicationCorresponds to variant rs9456735dbSNPEnsembl.1
Natural variantiVAR_019744211K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2. 5 PublicationsCorresponds to variant rs137853060dbSNPEnsembl.1
Natural variantiVAR_019746212C → Y in PARK2. 2 PublicationsCorresponds to variant rs137853058dbSNPEnsembl.1
Natural variantiVAR_019747240T → M in PARK2. 1 PublicationCorresponds to variant rs137853054dbSNPEnsembl.1
Natural variantiVAR_019748240T → R in PARK2; impairs the ability to ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; severely compromises the mitochondrial localization. 6 PublicationsCorresponds to variant rs137853054dbSNPEnsembl.1
Natural variantiVAR_019749253C → Y in PARK; late onset. 1 PublicationCorresponds to variant rs747427602dbSNPEnsembl.1
Natural variantiVAR_019750256R → C in PARK2 and PARK; at heterozygosity it is associated with late onset Parkinson disease; impairs the ability to ubiquitinate SNCAIP and ZNF746; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 7 PublicationsCorresponds to variant rs150562946dbSNPEnsembl.1
Natural variantiVAR_019752275R → W in PARK2 and PARK; at heterozygosity it is associated with late onset Parkinson disease; impairs the ability to ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional repression. 11 PublicationsCorresponds to variant rs34424986dbSNPEnsembl.1
Natural variantiVAR_019753280D → N in PARK; does not affect PINK-1 dependent localization to depolarized mitochondria. 3 PublicationsCorresponds to variant rs72480422dbSNPEnsembl.1
Natural variantiVAR_019754284G → R in PARK2. Corresponds to variant rs751037529dbSNPEnsembl.1
Natural variantiVAR_019755289C → G in PARK2; fails to ubiquitinate SYT11; loses ability to bind SYT11. 2 PublicationsCorresponds to variant rs55961220dbSNPEnsembl.1
Natural variantiVAR_019756328G → E in PARK2; does not affect PINK-1 dependent localization to depolarized mitochondria. 3 Publications1
Natural variantiVAR_019759351T → P in PARK2; impairs folding of IBR domain. 2 Publications1
Natural variantiVAR_070079402R → C in PARK2. 1 PublicationCorresponds to variant rs55830907dbSNPEnsembl.1
Natural variantiVAR_019763415T → N in PARK2; impairs the ability to ubiquitinate SNCAIP; does not affect turnover of CDCRE1; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria. 5 PublicationsCorresponds to variant rs778125254dbSNPEnsembl.1
Natural variantiVAR_070080418C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression; fails to ubiquitinate SYT11 but does not loose ability to bind SYT11. 3 Publications1
Natural variantiVAR_019764430G → D in PARK2; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria; impaired E3 ubiquitin-protein ligase toward ZNF746. 7 PublicationsCorresponds to variant rs191486604dbSNPEnsembl.1
Natural variantiVAR_019765431C → F in PARK2; impaired E3 ubiquitin-protein ligase toward ZNF746 and BCL2. 3 PublicationsCorresponds to variant rs397514694dbSNPEnsembl.1
Natural variantiVAR_019766437P → L in PARK2; impaired E3 ubiquitin-protein ligase toward BCL2. 5 PublicationsCorresponds to variant rs149953814dbSNPEnsembl.1
Natural variantiVAR_019767441C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 2 PublicationsCorresponds to variant rs778305273dbSNPEnsembl.1
Parkinson disease 2 (PARK2)19 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent.
See also OMIM:600116
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01973315V → M in PARK2. 1 PublicationCorresponds to variant rs532703934dbSNPEnsembl.1
Natural variantiVAR_01973433R → Q in PARK2. 1 PublicationCorresponds to variant rs147757966dbSNPEnsembl.1
Natural variantiVAR_01973537P → L in PARK2. 1 PublicationCorresponds to variant rs148990138dbSNPEnsembl.1
Natural variantiVAR_01973642R → P in PARK2; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding; Decreases ubiquitination and degradation. 5 PublicationsCorresponds to variant rs368134308dbSNPEnsembl.1
Natural variantiVAR_01973746A → P in PARK2. 1 Publication1
Natural variantiVAR_07007856V → E in PARK2. 1 PublicationCorresponds to variant rs137853059dbSNPEnsembl.1
Natural variantiVAR_01973882A → E in PARK2. 3 PublicationsCorresponds to variant rs55774500dbSNPEnsembl.1
Natural variantiVAR_01973992A → V in PARK2. Corresponds to variant rs566229879dbSNPEnsembl.1
Natural variantiVAR_019741161K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 5 PublicationsCorresponds to variant rs137853057dbSNPEnsembl.1
Natural variantiVAR_054107192M → L in PARK2; unknown pathological significance. 1 PublicationCorresponds to variant rs9456735dbSNPEnsembl.1
Natural variantiVAR_019743192M → V in PARK2; unknown pathological significance. 1 PublicationCorresponds to variant rs9456735dbSNPEnsembl.1
Natural variantiVAR_019744211K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2. 5 PublicationsCorresponds to variant rs137853060dbSNPEnsembl.1
Natural variantiVAR_019746212C → Y in PARK2. 2 PublicationsCorresponds to variant rs137853058dbSNPEnsembl.1
Natural variantiVAR_019747240T → M in PARK2. 1 PublicationCorresponds to variant rs137853054dbSNPEnsembl.1
Natural variantiVAR_019748240T → R in PARK2; impairs the ability to ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; severely compromises the mitochondrial localization. 6 PublicationsCorresponds to variant rs137853054dbSNPEnsembl.1
Natural variantiVAR_019750256R → C in PARK2 and PARK; at heterozygosity it is associated with late onset Parkinson disease; impairs the ability to ubiquitinate SNCAIP and ZNF746; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 7 PublicationsCorresponds to variant rs150562946dbSNPEnsembl.1
Natural variantiVAR_019752275R → W in PARK2 and PARK; at heterozygosity it is associated with late onset Parkinson disease; impairs the ability to ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional repression. 11 PublicationsCorresponds to variant rs34424986dbSNPEnsembl.1
Natural variantiVAR_019754284G → R in PARK2. Corresponds to variant rs751037529dbSNPEnsembl.1
Natural variantiVAR_019755289C → G in PARK2; fails to ubiquitinate SYT11; loses ability to bind SYT11. 2 PublicationsCorresponds to variant rs55961220dbSNPEnsembl.1
Natural variantiVAR_019756328G → E in PARK2; does not affect PINK-1 dependent localization to depolarized mitochondria. 3 Publications1
Natural variantiVAR_019759351T → P in PARK2; impairs folding of IBR domain. 2 Publications1
Natural variantiVAR_070079402R → C in PARK2. 1 PublicationCorresponds to variant rs55830907dbSNPEnsembl.1
Natural variantiVAR_019763415T → N in PARK2; impairs the ability to ubiquitinate SNCAIP; does not affect turnover of CDCRE1; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria. 5 PublicationsCorresponds to variant rs778125254dbSNPEnsembl.1
Natural variantiVAR_070080418C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression; fails to ubiquitinate SYT11 but does not loose ability to bind SYT11. 3 Publications1
Natural variantiVAR_019764430G → D in PARK2; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria; impaired E3 ubiquitin-protein ligase toward ZNF746. 7 PublicationsCorresponds to variant rs191486604dbSNPEnsembl.1
Natural variantiVAR_019765431C → F in PARK2; impaired E3 ubiquitin-protein ligase toward ZNF746 and BCL2. 3 PublicationsCorresponds to variant rs397514694dbSNPEnsembl.1
Natural variantiVAR_019766437P → L in PARK2; impaired E3 ubiquitin-protein ligase toward BCL2. 5 PublicationsCorresponds to variant rs149953814dbSNPEnsembl.1
Natural variantiVAR_019767441C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 2 PublicationsCorresponds to variant rs778305273dbSNPEnsembl.1

Defects in PARK2 may be involved in the development and/or progression of ovarian cancer.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi65S → E: Phosphomimetic mutant; still requires PINK1 for activation. PARK2 is activated in presence of phosphorylated ubiquitin. 2 Publications1
Mutagenesisi332C → S: Impairs folding of IBR domain. 1 Publication1
Mutagenesisi337C → A: Impairs the ability to ubiquitinate SNCAIP. 1 Publication1
Mutagenesisi365C → S: Impairs protein folding. 1 Publication1
Mutagenesisi403W → A: Decreased autoinhibition and increased E3 activity. 1 Publication1
Mutagenesisi421C → A: Impairs the ability of self-ubiquitination and to ubiquitinate SNCAIP. 2 Publications1
Mutagenesisi431C → S: Impairs the ability to ubiquitinate target proteins. 3 Publications1
Mutagenesisi433H → N or A: Impaired activity. 2 Publications1
Mutagenesisi444E → Q or A: Impaired activity. 2 Publications1

Keywords - Diseasei

Disease mutation, Neurodegeneration, Parkinson disease, Parkinsonism

Organism-specific databases

DisGeNETi5071.
MalaCardsiPARK2.
MIMi168600. phenotype.
600116. phenotype.
OpenTargetsiENSG00000185345.
Orphaneti2828. Young adult-onset Parkinsonism.
PharmGKBiPA32942.

Polymorphism and mutation databases

BioMutaiPARK2.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000585761 – 465E3 ubiquitin-protein ligase parkinAdd BLAST465

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei65Phosphoserine; by PINK13 Publications1

Post-translational modificationi

Auto-ubiquitinates in an E2-dependent manner leading to its own degradation (PubMed:19229105). Also polyubiquitinated by RNF41 for proteasomal degradation.1 Publication
S-nitrosylated. The inhibition of PARK2 ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of PARK2 substrates.1 Publication
Phosphorylation at Ser-65 by PINK1 contributes to activate PARK2 activity. It is however not sufficient and requires binding to phosphorylated ubiquitin as well.3 Publications

Keywords - PTMi

Phosphoprotein, S-nitrosylation, Ubl conjugation

Proteomic databases

PaxDbiO60260.
PeptideAtlasiO60260.
PRIDEiO60260.

PTM databases

iPTMnetiO60260.
PhosphoSitePlusiO60260.

Expressioni

Tissue specificityi

Highly expressed in the brain including the substantia nigra. Expressed in heart, testis and skeletal muscle. Expression is down-regulated or absent in tumor biopsies, and absent in the brain of PARK2 patients. Overexpression protects dopamine neurons from kainate-mediated apoptosis. Found in serum (at protein level).1 Publication

Gene expression databases

BgeeiENSG00000185345.
CleanExiHS_PARK2.
ExpressionAtlasiO60260. baseline and differential.
GenevisibleiO60260. HS.

Organism-specific databases

HPAiCAB016257.

Interactioni

Subunit structurei

Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PARK2, CUL1 and FBXW7. Interacts with SNCAIP. Binds to the C2A and C2B domains of SYT11. Interacts and regulates the turnover of SEPT5. Part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PARK2 and GPR37, thus facilitating PARK2-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PARK2, whereas, STUB1 enhances the E3 activity of PARK2 through promotion of dissociation of HSP70 from PARK2-GPR37 complexes. Interacts with PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2. Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination. Interacts (via first RING-type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and RNF41. Interacts with PINK1. Interacts with CHPF, the interaction with isoform 2 may facilitate PARK2 transport into the mitochondria. Interacts with MFN2 (phosphorylated), promotes PARK2 localization in dysfunctional depolarized mitochondria. Interacts with FBXO7; this promotes translocation to dysfunctional depolarized mitochondria. Interacts with heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria. Interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria. Forms a complex with PINK1 and PARK7 (PubMed:19229105).25 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself5EBI-716346,EBI-716346
Q99IB83EBI-716346,EBI-6858513From a different organism.
ATXN3P54252-25EBI-716346,EBI-9684323
CHPFQ8IZ52-25EBI-716346,EBI-9029620
FBXO7Q9Y3I110EBI-716346,EBI-1161222
FBXO7Q9Y3I1-12EBI-716346,EBI-9102965
LRRK2Q5S0073EBI-716346,EBI-5323863
PDCD2Q163425EBI-716346,EBI-359462
PINK1Q9BXM77EBI-716346,EBI-2846068
RANBP2P4979211EBI-716346,EBI-973138
RHOT1Q8IXI23EBI-716346,EBI-1396430
Sept5Q9Z2Q62EBI-716346,EBI-772125From a different organism.
TRIP13Q156453EBI-716346,EBI-358993
ZNF746Q6NUN96EBI-716346,EBI-3862525

GO - Molecular functioni

  • actin binding Source: ParkinsonsUK-UCL
  • beta-catenin binding Source: ParkinsonsUK-UCL
  • chaperone binding Source: BHF-UCL
  • cullin family protein binding Source: ParkinsonsUK-UCL
  • enzyme binding Source: ParkinsonsUK-UCL
  • F-box domain binding Source: ParkinsonsUK-UCL
  • G-protein coupled receptor binding Source: ParkinsonsUK-UCL
  • heat shock protein binding Source: ParkinsonsUK-UCL
  • histone deacetylase binding Source: ParkinsonsUK-UCL
  • Hsp70 protein binding Source: ParkinsonsUK-UCL
  • identical protein binding Source: IntAct
  • kinase binding Source: UniProtKB
  • PDZ domain binding Source: BHF-UCL
  • phospholipase binding Source: ParkinsonsUK-UCL
  • protein kinase binding Source: UniProtKB
  • SH3 domain binding Source: ParkinsonsUK-UCL
  • tubulin binding Source: ParkinsonsUK-UCL
  • ubiquitin binding Source: UniProtKB
  • ubiquitin conjugating enzyme binding Source: ParkinsonsUK-UCL
  • ubiquitin protein ligase binding Source: UniProtKB
  • ubiquitin-specific protease binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi111105. 421 interactors.
DIPiDIP-37655N.
IntActiO60260. 29 interactors.
MINTiMINT-1351124.
STRINGi9606.ENSP00000355865.

Structurei

Secondary structure

1465
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi2 – 11Combined sources10
Beta strandi13 – 16Combined sources4
Beta strandi19 – 21Combined sources3
Helixi23 – 34Combined sources12
Helixi38 – 40Combined sources3
Beta strandi41 – 45Combined sources5
Beta strandi48 – 50Combined sources3
Turni52 – 55Combined sources4
Helixi56 – 59Combined sources4
Beta strandi66 – 71Combined sources6
Beta strandi147 – 150Combined sources4
Turni152 – 154Combined sources3
Beta strandi156 – 166Combined sources11
Turni167 – 169Combined sources3
Beta strandi174 – 178Combined sources5
Helixi183 – 187Combined sources5
Beta strandi192 – 196Combined sources5
Beta strandi205 – 212Combined sources8
Beta strandi223 – 225Combined sources3
Turni239 – 241Combined sources3
Beta strandi246 – 250Combined sources5
Beta strandi257 – 260Combined sources4
Helixi261 – 273Combined sources13
Beta strandi278 – 280Combined sources3
Turni281 – 283Combined sources3
Beta strandi284 – 286Combined sources3
Helixi301 – 307Combined sources7
Helixi309 – 326Combined sources18
Turni335 – 337Combined sources3
Beta strandi348 – 351Combined sources4
Beta strandi354 – 356Combined sources3
Beta strandi363 – 365Combined sources3
Turni366 – 368Combined sources3
Beta strandi374 – 376Combined sources3
Helixi379 – 381Combined sources3
Helixi395 – 400Combined sources6
Beta strandi414 – 417Combined sources4
Turni419 – 421Combined sources3
Beta strandi424 – 426Combined sources3
Beta strandi429 – 431Combined sources3
Beta strandi433 – 435Combined sources3
Turni439 – 441Combined sources3
Beta strandi444 – 446Combined sources3
Turni447 – 449Combined sources3
Helixi455 – 461Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1IYFNMR-A1-76[»]
2JMONMR-A308-384[»]
4BM9X-ray2.25A137-465[»]
4I1FX-ray1.58A141-465[»]
4I1HX-ray2.00A141-465[»]
5C1ZX-ray1.79A/B1-465[»]
5C23X-ray2.37A/B1-465[»]
5C9VX-ray2.35A137-465[»]
ProteinModelPortaliO60260.
SMRiO60260.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO60260.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 76Ubiquitin-likePROSITE-ProRule annotationAdd BLAST76

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni204 – 238SYT11 binding 11 PublicationAdd BLAST35
Regioni257 – 293SYT11 binding 21 PublicationAdd BLAST37
Regioni378 – 410REPBy similarityAdd BLAST33

Domaini

The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes.1 Publication
The RING-type 1 zinc finger domain is required to repress p53/TP53 transcription.1 Publication
Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain (PubMed:21532592).1 Publication

Sequence similaritiesi

Belongs to the RBR family. Parkin subfamily.Curated
Contains 1 IBR-type zinc finger.Curated
Contains 3 RING-type zinc fingers.Curated
Contains 1 ubiquitin-like domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength