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O60260

- PRKN2_HUMAN

UniProt

O60260 - PRKN2_HUMAN

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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

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. cullin family protein binding Source: ParkinsonsUK-UCL
  3. F-box domain binding Source: ParkinsonsUK-UCL
  4. G-protein coupled receptor binding Source: ParkinsonsUK-UCL
  5. heat shock protein binding Source: ParkinsonsUK-UCL
  6. Hsp70 protein binding Source: ParkinsonsUK-UCL
  7. identical protein binding Source: IntAct
  8. kinase binding Source: BHF-UCL
  9. ligase activity Source: UniProtKB-KW
  10. PDZ domain binding Source: BHF-UCL
  11. protein kinase binding Source: UniProtKB
  12. SH3 domain binding Source: ParkinsonsUK-UCL
  13. ubiquitin binding Source: UniProtKB
  14. ubiquitin conjugating enzyme binding Source: ParkinsonsUK-UCL
  15. ubiquitin protein ligase activity Source: ParkinsonsUK-UCL
  16. ubiquitin protein ligase binding Source: UniProtKB
  17. ubiquitin-protein transferase activity Source: UniProtKB
  18. ubiquitin-specific protease binding Source: ParkinsonsUK-UCL
  19. zinc ion binding Source: ParkinsonsUK-UCL

GO - Biological processi

  1. adult locomotory behavior Source: Ensembl
  2. aggresome assembly Source: BHF-UCL
  3. cell death Source: UniProtKB-KW
  4. cellular protein catabolic process Source: ParkinsonsUK-UCL
  5. cellular response to dopamine Source: ParkinsonsUK-UCL
  6. cellular response to manganese ion Source: ParkinsonsUK-UCL
  7. cellular response to toxic substance Source: ParkinsonsUK-UCL
  8. cellular response to unfolded protein Source: ParkinsonsUK-UCL
  9. central nervous system development Source: ProtInc
  10. dopamine metabolic process Source: ParkinsonsUK-UCL
  11. dopamine uptake involved in synaptic transmission Source: Ensembl
  12. learning Source: Ensembl
  13. mitochondrion degradation Source: UniProtKB
  14. negative regulation of actin filament bundle assembly Source: BHF-UCL
  15. negative regulation of cell death Source: BHF-UCL
  16. negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
  17. negative regulation of glucokinase activity Source: MGI
  18. negative regulation of insulin secretion Source: MGI
  19. negative regulation of neuron apoptotic process Source: BHF-UCL
  20. negative regulation of neuron death Source: ParkinsonsUK-UCL
  21. negative regulation of oxidative stress-induced cell death Source: ParkinsonsUK-UCL
  22. negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
  23. negative regulation of protein phosphorylation Source: BHF-UCL
  24. negative regulation of reactive oxygen species metabolic process Source: ParkinsonsUK-UCL
  25. negative regulation of release of cytochrome c from mitochondria Source: BHF-UCL
  26. norepinephrine metabolic process Source: Ensembl
  27. positive regulation of DNA binding Source: ParkinsonsUK-UCL
  28. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
  29. positive regulation of mitochondrial fusion Source: ParkinsonsUK-UCL
  30. positive regulation of proteasomal protein catabolic process Source: ParkinsonsUK-UCL
  31. positive regulation of protein linear polyubiquitination Source: ParkinsonsUK-UCL
  32. positive regulation of transcription from RNA polymerase II promoter Source: ParkinsonsUK-UCL
  33. positive regulation of tumor necrosis factor-mediated signaling pathway Source: ParkinsonsUK-UCL
  34. proteasome-mediated ubiquitin-dependent protein catabolic process Source: ParkinsonsUK-UCL
  35. protein autoubiquitination Source: UniProtKB
  36. protein K27-linked ubiquitination Source: ParkinsonsUK-UCL
  37. protein K29-linked ubiquitination Source: ParkinsonsUK-UCL
  38. protein K48-linked ubiquitination Source: UniProtKB
  39. protein K63-linked ubiquitination Source: UniProtKB
  40. protein K6-linked ubiquitination Source: ParkinsonsUK-UCL
  41. protein monoubiquitination Source: UniProtKB
  42. protein polyubiquitination Source: UniProtKB
  43. protein ubiquitination Source: UniProtKB
  44. protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: UniProtKB
  45. regulation of autophagy Source: UniProtKB
  46. regulation of dopamine secretion Source: ParkinsonsUK-UCL
  47. regulation of glucose metabolic process Source: ParkinsonsUK-UCL
  48. regulation of lipid transport Source: ParkinsonsUK-UCL
  49. regulation of mitochondrion degradation Source: ParkinsonsUK-UCL
  50. regulation of mitochondrion organization Source: ParkinsonsUK-UCL
  51. regulation of neurotransmitter secretion Source: Ensembl
  52. regulation of reactive oxygen species metabolic process Source: UniProtKB
  53. regulation of synaptic vesicle transport Source: ParkinsonsUK-UCL
  54. response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  55. startle response Source: Ensembl
  56. synaptic transmission, glutamatergic Source: Ensembl
  57. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

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: ParkinsonsUK-UCL
  5. Golgi apparatus Source: UniProtKB
  6. Lewy body Source: ParkinsonsUK-UCL
  7. mitochondrion Source: UniProtKB
  8. neuron projection Source: Ensembl
  9. nucleus Source: ParkinsonsUK-UCL
  10. Parkin-FBXW7-Cul1 ubiquitin ligase complex Source: ParkinsonsUK-UCL
  11. perinuclear region of cytoplasm Source: UniProtKB
  12. ubiquitin ligase complex Source: UniProtKB
Complete GO annotation...

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

BgeeiO60260.
CleanExiHS_PARK2.
ExpressionAtlasiO60260. baseline and differential.
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
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

Protein-protein interaction databases

BioGridi111105. 397 interactions.
DIPiDIP-37655N.
IntActiO60260. 24 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.
GeneTreeiENSGT00390000011034.
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) [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

        10         20         30         40         50
MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL
60 70 80 90 100
RNDWTVQNCD LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ
110 120 130 140 150
SLTRVDLSSS VLPGDSVGLA VILHTDSRKD SPPAGSPAGR SIYNSFYVYC
160 170 180 190 200
KGPCQRVQPG KLRVQCSTCR QATLTLTQGP SCWDDVLIPN RMSGECQSPH
210 220 230 240 250
CPGTSAEFFF KCGAHPTSDK ETSVALHLIA TNSRNITCIT CTDVRSPVLV
260 270 280 290 300
FQCNSRHVIC LDCFHLYCVT RLNDRQFVHD PQLGYSLPCV AGCPNSLIKE
310 320 330 340 350
LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEPDQRKV
360 370 380 390 400
TCEGGNGLGC GFAFCRECKE AYHEGECSAV FEASGTTTQA YRVDERAAEQ
410 420 430 440 450
ARWEAASKET IKKTTKPCPR CHVPVEKNGG CMHMKCPQPQ CRLEWCWNCG
460
CEWNRVCMGD HWFDV
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