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O60260

- PRKN2_HUMAN

UniProt

O60260 - PRKN2_HUMAN

Protein

E3 ubiquitin-protein ligase parkin

Gene

PARK2

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 148 (01 Oct 2014)
      Sequence version 2 (17 Oct 2006)
      Previous versions | rss
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    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, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2. Mediates monoubiquitination as well as 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. 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. Mediates 'Lys-63'-linked polyubiquitination of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:24896179). 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. 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. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.21 Publications

    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:24784582).3 Publications

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei431 – 4311By similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri141 – 22585RING-type 0; atypicalAdd
    BLAST
    Zinc fingeri238 – 29356RING-type 1; atypicalAdd
    BLAST
    Zinc fingeri313 – 37765IBR-typeAdd
    BLAST
    Zinc fingeri418 – 44932RING-type 2Add
    BLAST

    GO - Molecular functioni

    1. chaperone binding Source: BHF-UCL
    2. identical protein binding Source: IntAct
    3. kinase binding Source: BHF-UCL
    4. ligase activity Source: UniProtKB-KW
    5. PDZ domain binding Source: BHF-UCL
    6. protein binding Source: UniProtKB
    7. protein kinase binding Source: UniProtKB
    8. ubiquitin binding Source: UniProtKB
    9. ubiquitin protein ligase activity Source: ParkinsonsUK-UCL
    10. ubiquitin protein ligase binding Source: UniProtKB
    11. ubiquitin-protein transferase activity Source: UniProtKB
    12. ubiquitin-specific protease binding Source: ParkinsonsUK-UCL
    13. zinc ion binding Source: InterPro

    GO - Biological processi

    1. aggresome assembly Source: BHF-UCL
    2. cell death Source: UniProtKB
    3. cellular protein catabolic process Source: ParkinsonsUK-UCL
    4. central nervous system development Source: ProtInc
    5. mitochondrion degradation Source: UniProtKB
    6. negative regulation of actin filament bundle assembly Source: BHF-UCL
    7. negative regulation of cell death Source: BHF-UCL
    8. negative regulation of glucokinase activity Source: MGI
    9. negative regulation of insulin secretion Source: MGI
    10. negative regulation of neuron apoptotic process Source: BHF-UCL
    11. negative regulation of neuron death Source: ParkinsonsUK-UCL
    12. negative regulation of protein phosphorylation Source: BHF-UCL
    13. negative regulation of release of cytochrome c from mitochondria Source: BHF-UCL
    14. neuron death Source: UniProtKB
    15. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
    16. proteasome-mediated ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
    17. protein autoubiquitination Source: UniProtKB
    18. protein K48-linked ubiquitination Source: UniProtKB
    19. protein K63-linked ubiquitination Source: UniProtKB
    20. protein monoubiquitination Source: UniProtKB
    21. protein polyubiquitination Source: UniProtKB
    22. protein ubiquitination Source: UniProtKB
    23. protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: UniProtKB
    24. regulation of autophagy Source: UniProtKB
    25. regulation of reactive oxygen species metabolic process Source: UniProtKB
    26. regulation of transcription, DNA-templated Source: UniProtKB-KW
    27. transcription, DNA-templated Source: UniProtKB-KW
    28. ubiquitin-dependent protein catabolic process Source: UniProtKB

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    Autophagy, Transcription, Transcription regulation, Ubl conjugation pathway

    Keywords - Ligandi

    Metal-binding, Zinc

    Enzyme and pathway databases

    ReactomeiREACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
    SignaLinkiO60260.
    UniPathwayiUPA00143.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    E3 ubiquitin-protein ligase parkin (EC:6.3.2.-)
    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
    ProteomesiUP000005640: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:8607. PARK2.

    Subcellular locationi

    Cytoplasmcytosol. Nucleus. Endoplasmic reticulum. Mitochondrion
    Note: Mainly localizes in the cytosol. Co-localizes with SYT11 in neutrites. Co-localizes with SNCAIP in brainstem Lewy bodies. Mitochondrial localization gradually increases with cellular growth. Also relocates to dysfunctional mitochondria that have lost the mitochondrial membrane potential; recruitment to mitochondria is PINK1-dependent.

    GO - Cellular componenti

    1. aggresome Source: BHF-UCL
    2. cytoplasm Source: UniProtKB
    3. cytosol Source: UniProtKB
    4. endoplasmic reticulum Source: UniProtKB-SubCell
    5. Golgi apparatus Source: UniProtKB
    6. mitochondrion Source: UniProtKB
    7. nucleus Source: ParkinsonsUK-UCL
    8. perinuclear region of cytoplasm Source: UniProtKB
    9. ubiquitin ligase complex Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Endoplasmic reticulum, Mitochondrion, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Parkinson disease (PARK) [MIM:168600]: A 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.2 Publications
    Note: 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).
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti15 – 151V → M in PARK2. 1 Publication
    VAR_019733
    Natural varianti33 – 331R → Q in PARK2. 1 Publication
    VAR_019734
    Natural varianti37 – 371P → L in PARK2. 1 Publication
    Corresponds to variant rs148990138 [ dbSNP | Ensembl ].
    VAR_019735
    Natural varianti42 – 421R → P in PARK2; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding. 2 Publications
    VAR_019736
    Natural varianti46 – 461A → P in PARK2. 1 Publication
    VAR_019737
    Natural varianti56 – 561V → E in PARK2. 1 Publication
    VAR_070078
    Natural varianti82 – 821A → E in PARK2. 3 Publications
    Corresponds to variant rs55774500 [ dbSNP | Ensembl ].
    VAR_019738
    Natural varianti92 – 921A → V in PARK2.
    VAR_019739
    Natural varianti161 – 1611K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 2 Publications
    VAR_019741
    Natural varianti192 – 1921M → L in PARK2; unknown pathological significance. 1 Publication
    Corresponds to variant rs9456735 [ dbSNP | Ensembl ].
    VAR_054107
    Natural varianti192 – 1921M → V in PARK2; unknown pathological significance. 1 Publication
    Corresponds to variant rs9456735 [ dbSNP | Ensembl ].
    VAR_019743
    Natural varianti211 – 2111K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2. 3 Publications
    VAR_019744
    Natural varianti211 – 2111K → R in PARK2. 1 Publication
    VAR_019745
    Natural varianti212 – 2121C → Y in PARK2. 2 Publications
    VAR_019746
    Natural varianti240 – 2401T → M in PARK2. 1 Publication
    VAR_019747
    Natural varianti240 – 2401T → R in PARK2; impairs the ability to ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; severely compromises the mitochondrial localization. 1 Publication
    VAR_019748
    Natural varianti253 – 2531C → Y in PARK; late onset. 1 Publication
    VAR_019749
    Natural varianti256 – 2561R → 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. 5 Publications
    Corresponds to variant rs150562946 [ dbSNP | Ensembl ].
    VAR_019750
    Natural varianti275 – 2751R → 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. 8 Publications
    Corresponds to variant rs34424986 [ dbSNP | Ensembl ].
    VAR_019752
    Natural varianti280 – 2801D → N in PARK; does not affect PINK-1 dependent localization to depolarized mitochondria. 2 Publications
    VAR_019753
    Natural varianti284 – 2841G → R in PARK2.
    VAR_019754
    Natural varianti289 – 2891C → G in PARK2; fails to ubiquitinate SYT11; loses ability to bind SYT11. 1 Publication
    Corresponds to variant rs55961220 [ dbSNP | Ensembl ].
    VAR_019755
    Natural varianti328 – 3281G → E in PARK2; does not affect PINK-1 dependent localization to depolarized mitochondria. 2 Publications
    VAR_019756
    Natural varianti334 – 3341R → C in PARK2. 1 Publication
    VAR_019757
    Natural varianti351 – 3511T → P in PARK2; impairs folding of IBR domain. 1 Publication
    VAR_019759
    Natural varianti402 – 4021R → C in PARK2. 1 Publication
    VAR_070079
    Natural varianti415 – 4151T → N in PARK2; impairs the ability to ubiquitinate SNCAIP; does not affect turnover of CDCRE1; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria. 3 Publications
    VAR_019763
    Natural varianti418 – 4181C → 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. 1 Publication
    VAR_070080
    Natural varianti430 – 4301G → D in PARK2; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria; impaired E3 ubiquitin-protein ligase toward ZNF746. 5 Publications
    VAR_019764
    Natural varianti431 – 4311C → F in PARK2; impaired E3 ubiquitin-protein ligase toward ZNF746 and BCL2. 1 Publication
    VAR_019765
    Natural varianti437 – 4371P → L in PARK2; impaired E3 ubiquitin-protein ligase toward BCL2. 4 Publications
    Corresponds to variant rs149953814 [ dbSNP | Ensembl ].
    VAR_019766
    Natural varianti441 – 4411C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 1 Publication
    VAR_019767
    Parkinson disease 2 (PARK2) [MIM:600116]: A 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.19 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti15 – 151V → M in PARK2. 1 Publication
    VAR_019733
    Natural varianti33 – 331R → Q in PARK2. 1 Publication
    VAR_019734
    Natural varianti37 – 371P → L in PARK2. 1 Publication
    Corresponds to variant rs148990138 [ dbSNP | Ensembl ].
    VAR_019735
    Natural varianti42 – 421R → P in PARK2; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding. 2 Publications
    VAR_019736
    Natural varianti46 – 461A → P in PARK2. 1 Publication
    VAR_019737
    Natural varianti56 – 561V → E in PARK2. 1 Publication
    VAR_070078
    Natural varianti82 – 821A → E in PARK2. 3 Publications
    Corresponds to variant rs55774500 [ dbSNP | Ensembl ].
    VAR_019738
    Natural varianti92 – 921A → V in PARK2.
    VAR_019739
    Natural varianti161 – 1611K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 2 Publications
    VAR_019741
    Natural varianti192 – 1921M → L in PARK2; unknown pathological significance. 1 Publication
    Corresponds to variant rs9456735 [ dbSNP | Ensembl ].
    VAR_054107
    Natural varianti192 – 1921M → V in PARK2; unknown pathological significance. 1 Publication
    Corresponds to variant rs9456735 [ dbSNP | Ensembl ].
    VAR_019743
    Natural varianti211 – 2111K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2. 3 Publications
    VAR_019744
    Natural varianti211 – 2111K → R in PARK2. 1 Publication
    VAR_019745
    Natural varianti212 – 2121C → Y in PARK2. 2 Publications
    VAR_019746
    Natural varianti240 – 2401T → M in PARK2. 1 Publication
    VAR_019747
    Natural varianti240 – 2401T → R in PARK2; impairs the ability to ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; severely compromises the mitochondrial localization. 1 Publication
    VAR_019748
    Natural varianti256 – 2561R → 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. 5 Publications
    Corresponds to variant rs150562946 [ dbSNP | Ensembl ].
    VAR_019750
    Natural varianti275 – 2751R → 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. 8 Publications
    Corresponds to variant rs34424986 [ dbSNP | Ensembl ].
    VAR_019752
    Natural varianti284 – 2841G → R in PARK2.
    VAR_019754
    Natural varianti289 – 2891C → G in PARK2; fails to ubiquitinate SYT11; loses ability to bind SYT11. 1 Publication
    Corresponds to variant rs55961220 [ dbSNP | Ensembl ].
    VAR_019755
    Natural varianti328 – 3281G → E in PARK2; does not affect PINK-1 dependent localization to depolarized mitochondria. 2 Publications
    VAR_019756
    Natural varianti334 – 3341R → C in PARK2. 1 Publication
    VAR_019757
    Natural varianti351 – 3511T → P in PARK2; impairs folding of IBR domain. 1 Publication
    VAR_019759
    Natural varianti402 – 4021R → C in PARK2. 1 Publication
    VAR_070079
    Natural varianti415 – 4151T → N in PARK2; impairs the ability to ubiquitinate SNCAIP; does not affect turnover of CDCRE1; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria. 3 Publications
    VAR_019763
    Natural varianti418 – 4181C → 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. 1 Publication
    VAR_070080
    Natural varianti430 – 4301G → D in PARK2; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria; impaired E3 ubiquitin-protein ligase toward ZNF746. 5 Publications
    VAR_019764
    Natural varianti431 – 4311C → F in PARK2; impaired E3 ubiquitin-protein ligase toward ZNF746 and BCL2. 1 Publication
    VAR_019765
    Natural varianti437 – 4371P → L in PARK2; impaired E3 ubiquitin-protein ligase toward BCL2. 4 Publications
    Corresponds to variant rs149953814 [ dbSNP | Ensembl ].
    VAR_019766
    Natural varianti441 – 4411C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 1 Publication
    VAR_019767
    Defects in PARK2 may be involved in the development and/or progression of ovarian cancer.

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi65 – 651S → E: Phosphomimetic mutant; still requires PINK1 for activation. PARK2 is activated in presence of phosphorylated ubiquitin. 1 Publication
    Mutagenesisi332 – 3321C → S: Impairs folding of IBR domain. 1 Publication
    Mutagenesisi337 – 3371C → A: Impairs the ability to ubiquitinate SNCAIP. 1 Publication
    Mutagenesisi365 – 3651C → S: Impairs protein folding. 1 Publication
    Mutagenesisi403 – 4031W → A: Decreased autoinhibition and increased E3 activity. 1 Publication
    Mutagenesisi421 – 4211C → A: Impairs the ability of self-ubiquitination and to ubiquitinate SNCAIP. 2 Publications
    Mutagenesisi431 – 4311C → S: Impairs the ability to ubiquitinate target proteins. 3 Publications
    Mutagenesisi433 – 4331H → N or A: Impaired activity. 2 Publications
    Mutagenesisi444 – 4441E → Q or A: Impaired activity. 2 Publications

    Keywords - Diseasei

    Disease mutation, Neurodegeneration, Parkinson disease, Parkinsonism

    Organism-specific databases

    MIMi168600. phenotype.
    600116. phenotype.
    Orphaneti2828. Young adult-onset Parkinsonism.
    PharmGKBiPA32942.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 465465E3 ubiquitin-protein ligase parkinPRO_0000058576Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei65 – 651Phosphoserine; by PINK12 Publications

    Post-translational modificationi

    Auto-ubiquitinates in an E2-dependent manner leading to its own degradation. Also polyubiquitinated by RNF41 for proteasomal degradation.
    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.2 Publications

    Keywords - PTMi

    Phosphoprotein, S-nitrosylation, Ubl conjugation

    Proteomic databases

    PaxDbiO60260.
    PRIDEiO60260.

    PTM databases

    PhosphoSiteiO60260.

    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

    ArrayExpressiO60260.
    BgeeiO60260.
    CleanExiHS_PARK2.
    GenevestigatoriO60260.

    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.24 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    itself5EBI-716346,EBI-716346
    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

    Protein-protein interaction databases

    BioGridi111105. 380 interactions.
    DIPiDIP-37655N.
    IntActiO60260. 23 interactions.
    MINTiMINT-1351124.
    STRINGi9606.ENSP00000355865.

    Structurei

    Secondary structure

    1
    465
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi2 – 76
    Turni8 – 103
    Beta strandi11 – 177
    Beta strandi19 – 213
    Helixi23 – 3311
    Beta strandi38 – 458
    Beta strandi48 – 503
    Turni52 – 554
    Helixi57 – 604
    Beta strandi63 – 708
    Beta strandi147 – 1504
    Turni152 – 1543
    Beta strandi156 – 16611
    Turni167 – 1693
    Beta strandi174 – 1785
    Helixi183 – 1875
    Beta strandi192 – 1965
    Beta strandi205 – 2128
    Beta strandi223 – 2253
    Turni239 – 2413
    Beta strandi246 – 2505
    Beta strandi257 – 2604
    Helixi261 – 27313
    Beta strandi278 – 2803
    Turni281 – 2833
    Beta strandi284 – 2863
    Helixi301 – 3077
    Helixi309 – 32618
    Turni335 – 3373
    Beta strandi348 – 3514
    Beta strandi354 – 3563
    Beta strandi363 – 3653
    Turni366 – 3683
    Beta strandi374 – 3763
    Helixi379 – 3813
    Helixi395 – 4006
    Beta strandi414 – 4174
    Turni419 – 4213
    Beta strandi424 – 4263
    Beta strandi429 – 4313
    Beta strandi433 – 4353
    Turni439 – 4413
    Beta strandi444 – 4463
    Turni447 – 4493
    Helixi455 – 4617

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1IYFNMR-A1-76[»]
    2JMONMR-A308-384[»]
    4BM9X-ray2.25A137-465[»]
    4I1FX-ray1.58A141-465[»]
    4I1HX-ray2.00A141-465[»]
    ProteinModelPortaliO60260.
    SMRiO60260. Positions 1-76, 141-465.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO60260.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini1 – 7676Ubiquitin-likePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni204 – 23835SYT11 binding 1Add
    BLAST
    Regioni257 – 29337SYT11 binding 2Add
    BLAST
    Regioni378 – 41033REPBy similarityAdd
    BLAST

    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

    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)LengthDescriptionGraphical viewFeature identifierActions
    Zinc fingeri141 – 22585RING-type 0; atypicalAdd
    BLAST
    Zinc fingeri238 – 29356RING-type 1; atypicalAdd
    BLAST
    Zinc fingeri313 – 37765IBR-typeAdd
    BLAST
    Zinc fingeri418 – 44932RING-type 2Add
    BLAST

    Keywords - Domaini

    Repeat, Zinc-finger

    Phylogenomic databases

    eggNOGiNOG278133.
    HOVERGENiHBG053682.
    InParanoidiO60260.
    KOiK04556.
    OMAiSTKPCPK.
    OrthoDBiEOG738054.
    PhylomeDBiO60260.
    TreeFamiTF314529.

    Family and domain databases

    InterProiIPR003977. Parkin.
    IPR000626. Ubiquitin-like.
    IPR029071. Ubiquitin-rel_dom.
    IPR002867. Znf_C6HC.
    [Graphical view]
    PfamiPF01485. IBR. 2 hits.
    PF00240. ubiquitin. 1 hit.
    [Graphical view]
    PIRSFiPIRSF037880. Parkin. 1 hit.
    PRINTSiPR01475. PARKIN.
    SMARTiSM00647. IBR. 2 hits.
    SM00213. UBQ. 1 hit.
    [Graphical view]
    SUPFAMiSSF54236. SSF54236. 1 hit.
    PROSITEiPS50053. UBIQUITIN_2. 1 hit.
    [Graphical view]

    Sequences (8)i

    Sequence statusi: Complete.

    This entry describes 8 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: O60260-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL    50
    RNDWTVQNCD LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ 100
    SLTRVDLSSS VLPGDSVGLA VILHTDSRKD SPPAGSPAGR SIYNSFYVYC 150
    KGPCQRVQPG KLRVQCSTCR QATLTLTQGP SCWDDVLIPN RMSGECQSPH 200
    CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT CTDVRSPVLV 250
    FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE 300
    LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV 350
    TCEGGNGLGC GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ 400
    ARWEAASKET IKKTTKPCPR CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG 450
    CEWNRVCMGD HWFDV 465
    Length:465
    Mass (Da):51,641
    Last modified:October 17, 2006 - v2
    Checksum:i9A8BB802A3FC84C3
    GO
    Isoform 2 (identifier: O60260-2) [UniParc]FASTAAdd to Basket

    Also known as: SV5DEL

    The sequence of this isoform differs from the canonical sequence as follows:
         179-206: Missing.

    Show »
    Length:437
    Mass (Da):48,713
    Checksum:iA435AF6495DED559
    GO
    Isoform 3 (identifier: O60260-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-79: Missing.
         291-297: AGCPNSL → VCLLPGM
         298-465: Missing.

    Show »
    Length:218
    Mass (Da):23,639
    Checksum:i4CB1B7EBD8A25F4B
    GO
    Isoform 4 (identifier: O60260-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-191: Missing.

    Show »
    Length:274
    Mass (Da):30,616
    Checksum:iCAE5D2F530395FA1
    GO
    Isoform 5 (identifier: O60260-5) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         290-290: V → VGTGDTVVLRGALGGFRRGV
         362-368: FAFCREC → YGQRRTK
         369-465: Missing.

    Show »
    Length:387
    Mass (Da):42,407
    Checksum:i48C0F41C86226606
    GO
    Isoform 6 (identifier: O60260-6) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         58-206: Missing.

    Show »
    Length:316
    Mass (Da):35,631
    Checksum:i4AE7F62C46499A24
    GO
    Isoform 7 (identifier: O60260-7) [UniParc]FASTAAdd to Basket

    Also known as: SV5,9DEL

    The sequence of this isoform differs from the canonical sequence as follows:
         179-206: Missing.
         312-361: Missing.

    Show »
    Length:387
    Mass (Da):43,485
    Checksum:i0521F623B06DDDE6
    GO
    Isoform 8 (identifier: O60260-8) [UniParc]FASTAAdd to Basket

    Also known as: SV9DEL

    The sequence of this isoform differs from the canonical sequence as follows:
         312-361: Missing.

    Show »
    Length:415
    Mass (Da):46,413
    Checksum:i0EF24F73366A6454
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti223 – 2231S → P in BAA25751. (PubMed:9560156)Curated
    Sequence conflicti223 – 2231S → P in AAM21458. 1 PublicationCurated
    Sequence conflicti223 – 2231S → P in AAM21457. 1 PublicationCurated
    Sequence conflicti289 – 2902CV → MI in AAM21461. (PubMed:19501131)Curated
    Sequence conflicti339 – 3391A → V in AAS88422. 1 PublicationCurated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti15 – 151V → M in PARK2. 1 Publication
    VAR_019733
    Natural varianti33 – 331R → Q in PARK2. 1 Publication
    VAR_019734
    Natural varianti37 – 371P → L in PARK2. 1 Publication
    Corresponds to variant rs148990138 [ dbSNP | Ensembl ].
    VAR_019735
    Natural varianti42 – 421R → P in PARK2; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding. 2 Publications
    VAR_019736
    Natural varianti46 – 461A → P in PARK2. 1 Publication
    VAR_019737
    Natural varianti56 – 561V → E in PARK2. 1 Publication
    VAR_070078
    Natural varianti82 – 821A → E in PARK2. 3 Publications
    Corresponds to variant rs55774500 [ dbSNP | Ensembl ].
    VAR_019738
    Natural varianti92 – 921A → V in PARK2.
    VAR_019739
    Natural varianti100 – 1001Q → H.1 Publication
    VAR_019740
    Natural varianti161 – 1611K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 2 Publications
    VAR_019741
    Natural varianti167 – 1671S → N.4 Publications
    Corresponds to variant rs1801474 [ dbSNP | Ensembl ].
    VAR_019742
    Natural varianti192 – 1921M → L in PARK2; unknown pathological significance. 1 Publication
    Corresponds to variant rs9456735 [ dbSNP | Ensembl ].
    VAR_054107
    Natural varianti192 – 1921M → V in PARK2; unknown pathological significance. 1 Publication
    Corresponds to variant rs9456735 [ dbSNP | Ensembl ].
    VAR_019743
    Natural varianti211 – 2111K → N in PARK2; severely compromises the mitochondrial localization; fails to stabilize BCL2. 3 Publications
    VAR_019744
    Natural varianti211 – 2111K → R in PARK2. 1 Publication
    VAR_019745
    Natural varianti212 – 2121C → Y in PARK2. 2 Publications
    VAR_019746
    Natural varianti240 – 2401T → M in PARK2. 1 Publication
    VAR_019747
    Natural varianti240 – 2401T → R in PARK2; impairs the ability to ubiquitinate SNCAIP and BCL2; loss of UBE2L3 binding; severely compromises the mitochondrial localization. 1 Publication
    VAR_019748
    Natural varianti253 – 2531C → Y in PARK; late onset. 1 Publication
    VAR_019749
    Natural varianti256 – 2561R → 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. 5 Publications
    Corresponds to variant rs150562946 [ dbSNP | Ensembl ].
    VAR_019750
    Natural varianti271 – 2711R → S.1 Publication
    VAR_019751
    Natural varianti275 – 2751R → 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. 8 Publications
    Corresponds to variant rs34424986 [ dbSNP | Ensembl ].
    VAR_019752
    Natural varianti280 – 2801D → N in PARK; does not affect PINK-1 dependent localization to depolarized mitochondria. 2 Publications
    VAR_019753
    Natural varianti284 – 2841G → R in PARK2.
    VAR_019754
    Natural varianti289 – 2891C → G in PARK2; fails to ubiquitinate SYT11; loses ability to bind SYT11. 1 Publication
    Corresponds to variant rs55961220 [ dbSNP | Ensembl ].
    VAR_019755
    Natural varianti311 – 3111Q → R in a patient with Parkinson disease; unknown pathological significance. 1 Publication
    VAR_062672
    Natural varianti328 – 3281G → E in PARK2; does not affect PINK-1 dependent localization to depolarized mitochondria. 2 Publications
    VAR_019756
    Natural varianti334 – 3341R → C in PARK2. 1 Publication
    VAR_019757
    Natural varianti339 – 3391A → S.1 Publication
    VAR_019758
    Natural varianti351 – 3511T → P in PARK2; impairs folding of IBR domain. 1 Publication
    VAR_019759
    Natural varianti366 – 3661R → W.1 Publication
    Corresponds to variant rs56092260 [ dbSNP | Ensembl ].
    VAR_019760
    Natural varianti371 – 3711A → T in a patient with Parkinson disease; unknown pathological significance. 1 Publication
    VAR_062673
    Natural varianti380 – 3801V → L.4 Publications
    Corresponds to variant rs1801582 [ dbSNP | Ensembl ].
    VAR_019761
    Natural varianti394 – 3941D → N.3 Publications
    Corresponds to variant rs1801334 [ dbSNP | Ensembl ].
    VAR_019762
    Natural varianti402 – 4021R → C in PARK2. 1 Publication
    VAR_070079
    Natural varianti415 – 4151T → N in PARK2; impairs the ability to ubiquitinate SNCAIP; does not affect turnover of CDCRE1; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria. 3 Publications
    VAR_019763
    Natural varianti418 – 4181C → 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. 1 Publication
    VAR_070080
    Natural varianti430 – 4301G → D in PARK2; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria; impaired E3 ubiquitin-protein ligase toward ZNF746. 5 Publications
    VAR_019764
    Natural varianti431 – 4311C → F in PARK2; impaired E3 ubiquitin-protein ligase toward ZNF746 and BCL2. 1 Publication
    VAR_019765
    Natural varianti437 – 4371P → L in PARK2; impaired E3 ubiquitin-protein ligase toward BCL2. 4 Publications
    Corresponds to variant rs149953814 [ dbSNP | Ensembl ].
    VAR_019766
    Natural varianti441 – 4411C → R in PARK2; decreased binding to the TP53 promoter; abolishes TP53 transcriptional repression. 1 Publication
    VAR_019767

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 191191Missing in isoform 4. 1 PublicationVSP_011705Add
    BLAST
    Alternative sequencei1 – 7979Missing in isoform 3. 1 PublicationVSP_011706Add
    BLAST
    Alternative sequencei58 – 206149Missing in isoform 6. CuratedVSP_041563Add
    BLAST
    Alternative sequencei179 – 20628Missing in isoform 2 and isoform 7. 2 PublicationsVSP_011707Add
    BLAST
    Alternative sequencei290 – 2901V → VGTGDTVVLRGALGGFRRGV in isoform 5. 1 PublicationVSP_011708