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Q9WVS6 (PRKN2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 115. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase parkin

EC=6.3.2.-
Gene names
Name:Park2
Synonyms:Prkn
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length464 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform ofSNCAIP, SEPT5, 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), potentially by the ubiquitination of mitochondrial proteins. 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. Ref.5 Ref.6 Ref.7

Enzyme regulation

In the autoinhibited state the side chain of Phe-462 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-430, whereas the REP repressor element binds RING-1 and blocks its E2-binding site By similarity.

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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 FBXO7; this promotes translocation to dysfunctional depolarized mitochondria By similarity. 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 LRKK2. 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 may facilitate PARK2 transport into the mitochondria. Interacts with MFN2 (phosphorylated), promotes PARK2 localization in dysfunctional depolarized mitochondria. Interacts with heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria By similarity. Interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria By similarity. Ref.7

Subcellular location

Nucleus By similarity. Endoplasmic reticulum By similarity. Cytoplasmcytosol Probable. Cell projectiondendrite By similarity. Cell junctionsynapsepostsynaptic cell membranepostsynaptic density By similarity. Mitochondrion By similarity. Cell junctionsynapse By similarity. Note: Mainly localizes in the cytosol. Expressed in the endoplasmic reticulum, dendrites, some presynaptic terminals and in postsynaptic densities. Relocates to dysfunctional mitochondria that have lost the mitochondial membrane potential; recruitment to mitochondria is PINK1-dependent By similarity. Ref.1 Ref.2

Tissue specificity

Expressed in all subdivisions of the brain. Highly expressed in brainstem, cranial nerve, pontine, cerebellar nuclei, indusium griseum, nuclei reticularis, strata oriens and laccunosum moleculare of the hippocampal CA2 region. Low levels were found in the telencephalon and diencephalon. Expressed in heart, liver, skeletal muscle, kidney and testis. Ref.1 Ref.2 Ref.4

Developmental stage

In late 10 dpc weakly expressed in postmitotic neurons in the mantle layer of the developing nervous system. Expression increased at 11-12 dpc. At 15-16 dpc, as more specialized neurons and nonneural cells are formed, expression is more tissue specific. Expression was highest in the neurites, moderate levels were observed in the migrating postmitotic neurons in the intermediate and neopallial layers. In the diencephalon and other CNS regions, while the weakest level of expression was observed in the cell bodies. In nonneural tissues, high levels of expression were found in the muscle walls of the intestine, the blood vessels and the dermis. Ref.4

Domain

The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes By similarity.

The RING-type 1 zinc finger domain is required to repress p53/TP53 transcription By similarity.

Post-translational modification

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

S-nitrosylated.

Disruption phenotype

In brain, increased protein levels of p53/TP53 and CHPF. Ref.6 Ref.7

Miscellaneous

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 By similarity.

Sequence similarities

Belongs to the RBR family. Parkin subfamily.

Contains 1 IBR-type zinc finger.

Contains 3 RING-type zinc fingers.

Contains 1 ubiquitin-like domain.

Ontologies

Keywords
   Biological processAutophagy
Transcription
Transcription regulation
Ubl conjugation pathway
   Cellular componentCell junction
Cell membrane
Cell projection
Cytoplasm
Endoplasmic reticulum
Membrane
Mitochondrion
Nucleus
Postsynaptic cell membrane
Synapse
   Coding sequence diversityAlternative splicing
   DomainRepeat
Zinc-finger
   LigandMetal-binding
Zinc
   Molecular functionLigase
   PTMS-nitrosylation
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processadult locomotory behavior

Inferred from mutant phenotype PubMed 18346797. Source: MGI

cell death

Inferred from sequence or structural similarity. Source: UniProtKB

dopamine metabolic process

Inferred from mutant phenotype PubMed 12915482. Source: MGI

dopamine uptake involved in synaptic transmission

Inferred from mutant phenotype PubMed 12915482. Source: MGI

learning

Inferred from mutant phenotype PubMed 12915482. Source: MGI

locomotory behavior

Inferred from mutant phenotype PubMed 12915482PubMed 12930822PubMed 15882845. Source: MGI

mitochondrion degradation

Inferred from sequence or structural similarity. Source: UniProtKB

neuron death

Inferred from sequence or structural similarity. Source: UniProtKB

norepinephrine metabolic process

Inferred from mutant phenotype PubMed 15249681. Source: MGI

protein K48-linked ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein metabolic process

Inferred from mutant phenotype PubMed 14985362. Source: MGI

protein monoubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of autophagy

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of neurotransmitter secretion

Inferred from mutant phenotype PubMed 12930822. Source: MGI

regulation of synaptic transmission

Inferred from mutant phenotype PubMed 12930822. Source: MGI

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

startle response

Inferred from mutant phenotype PubMed 15249681. Source: MGI

synaptic transmission, dopaminergic

Inferred from mutant phenotype PubMed 12915482. Source: MGI

synaptic transmission, glutamatergic

Inferred from mutant phenotype PubMed 12915482. Source: MGI

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

ubiquitin-dependent protein catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcell junction

Inferred from electronic annotation. Source: UniProtKB-KW

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Inferred from sequence or structural similarity. Source: UniProtKB

dendrite

Inferred from electronic annotation. Source: UniProtKB-SubCell

endoplasmic reticulum

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrion

Inferred from sequence or structural similarity. Source: UniProtKB

neuron projection

Inferred from direct assay Ref.4. Source: MGI

nucleus

Inferred from direct assay PubMed 24187134. Source: MGI

postsynaptic density

Inferred from electronic annotation. Source: UniProtKB-SubCell

postsynaptic membrane

Inferred from electronic annotation. Source: UniProtKB-KW

protein complex

Inferred from direct assay PubMed 18190519. Source: MGI

   Molecular_functionprotein binding

Inferred from physical interaction PubMed 21376232. Source: UniProtKB

ubiquitin-protein transferase activity

Inferred from direct assay PubMed 20064468. Source: MGI

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9WVS6-1)

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.
Isoform 2 (identifier: Q9WVS6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     245-254: SPVLVFQCNH → FMRMSKHRTS
     255-464: Missing.
Isoform 3 (identifier: Q9WVS6-3)

The sequence of this isoform differs from the canonical sequence as follows:
     244-261: RSPVLVFQCNHRHVICLD → SHLPLSSGASVWTRPHLH
     262-464: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 464464E3 ubiquitin-protein ligase parkin
PRO_0000058577

Regions

Domain1 – 7676Ubiquitin-like
Zinc finger140 – 22485RING-type 0; atypical
Zinc finger237 – 29256RING-type 1; atypical
Zinc finger312 – 37665IBR-type
Zinc finger417 – 44832RING-type 2
Region204 – 23835SYT11 binding 1
Region257 – 29337SYT11 binding 2
Region377 – 40933REP By similarity

Sites

Active site4301 By similarity

Natural variations

Alternative sequence244 – 26118RSPVL…VICLD → SHLPLSSGASVWTRPHLH in isoform 3.
VSP_011713
Alternative sequence245 – 25410SPVLVFQCNH → FMRMSKHRTS in isoform 2.
VSP_011714
Alternative sequence255 – 464210Missing in isoform 2.
VSP_011715
Alternative sequence262 – 464203Missing in isoform 3.
VSP_011716

Experimental info

Sequence conflict1371P → PA Ref.1
Sequence conflict1371P → PA in AAG13890. Ref.2

Secondary structure

............... 464
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: 5574A285A9A1B080

FASTA46451,618
        10         20         30         40         50         60 
MIVFVRFNSS YGFPVEVDSD TSILQLKEVV AKRQGVPADQ LRVIFAGKEL PNHLTVQNCD 

        70         80         90        100        110        120 
LEQQSIVHIV QRPRRRSHET NASGGDEPQS TSEGSIWESR SLTRVDLSSH TLPVDSVGLA 

       130        140        150        160        170        180 
VILDTDSKRD SEAARGPVKP TYNSFFIYCK GPCHKVQPGK LRVQCGTCKQ ATLTLAQGPS 

       190        200        210        220        230        240 
CWDDVLIPNR MSGECQSPDC PGTRAEFFFK CGAHPTSDKD TSVALNLITS NRRSIPCIAC 

       250        260        270        280        290        300 
TDVRSPVLVF QCNHRHVICL DCFHLYCVTR LNDRQFVHDA QLGYSLPCVA GCPNSLIKEL 

       310        320        330        340        350        360 
HHFRILGEEQ YTRYQQYGAE ECVLQMGGVL CPRPGCGAGL LPEQGQRKVT CEGGNGLGCG 

       370        380        390        400        410        420 
FVFCRDCKEA YHEGDCDSLL EPSGATSQAY RVDKRAAEQA RWEEASKETI KKTTKPCPRC 

       430        440        450        460 
NVPIEKNGGC MHMKCPQPQC KLEWCWNCGC EWNRACMGDH WFDV 

« Hide

Isoform 2 [UniParc].

Checksum: 3D35E959C9C5ED03
Show »

FASTA25428,084
Isoform 3 [UniParc].

Checksum: 6DA482E28FE80671
Show »

FASTA26128,629

References

« Hide 'large scale' references
[1]"Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene."
Kitada T., Asakawa S., Minoshima S., Mizuno Y., Shimizu N.
Mamm. Genome 11:417-421(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
Tissue: Skeletal muscle.
[2]"Parkin expression in the adult mouse brain."
Stichel C.C., Augustin M., Kuehn K., Zhu X.-R., Engels P., Ullmer C., Luebbert H.
Eur. J. Neurosci. 12:4181-4194(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
Strain: BALB/c.
Tissue: Kidney.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[4]"Differential expression and tissue distribution of parkin isoforms during mouse development."
Huynh D.P., Dy M., Nguyen D., Kiehl T.-R., Pulst S.M.
Brain Res. Dev. Brain Res. 130:173-181(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[5]"S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function."
Chung K.K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C., Marsh L., Dawson V.L., Dawson T.M.
Science 304:1328-1331(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN UBIQUITINATION, S-NITROSYLATION.
[6]"Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease."
da Costa C.A., Sunyach C., Giaime E., West A., Corti O., Brice A., Safe S., Abou-Sleiman P.M., Wood N.W., Takahashi H., Goldberg M.S., Shen J., Checler F.
Nat. Cell Biol. 11:1370-1375(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN APOPTOSIS, DISRUPTION PHENOTYPE.
[7]"Parkin interacts with Klokin1 for mitochondrial import and maintenance of membrane potential."
Kuroda Y., Sako W., Goto S., Sawada T., Uchida D., Izumi Y., Takahashi T., Kagawa N., Matsumoto M., Matsumoto M., Takahashi R., Kaji R., Mitsui T.
Hum. Mol. Genet. 21:991-1003(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH CHPF, DISRUPTION PHENOTYPE.
[8]"NMR structure of ubiquitin-like domain in PARKIN: gene product of familial Parkinson's disease."
Tashiro M., Okubo S., Shimotakahara S., Hatanaka H., Yasuda H., Kainosho M., Yokoyama S., Shindo H.
J. Biomol. NMR 25:153-156(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 1-76.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB019558 mRNA. Translation: BAA82404.1.
AF250293 mRNA. Translation: AAG13890.1.
AF250294 mRNA. Translation: AAG13891.1.
AF250295 mRNA. Translation: AAG13892.1.
BC113204 mRNA. Translation: AAI13205.1.
RefSeqNP_057903.1. NM_016694.3. [Q9WVS6-1]
XP_006523403.1. XM_006523340.1.
UniGeneMm.311110.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1MG8NMR-A1-76[»]
2ZEQX-ray1.65A1-76[»]
3B1LX-ray1.85X1-76[»]
ProteinModelPortalQ9WVS6.
SMRQ9WVS6. Positions 1-76, 140-464.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid206136. 17 interactions.
IntActQ9WVS6. 8 interactions.
MINTMINT-2736580.
STRING10090.ENSMUSP00000063644.

PTM databases

PhosphoSiteQ9WVS6.

Proteomic databases

PRIDEQ9WVS6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID50873.
KEGGmmu:50873.
UCSCuc008akj.1. mouse. [Q9WVS6-3]
uc008akk.1. mouse. [Q9WVS6-1]

Organism-specific databases

CTD5071.
MGIMGI:1355296. Park2.

Phylogenomic databases

eggNOGNOG278133.
HOGENOMHOG000013184.
HOVERGENHBG053682.
InParanoidQ2KHJ9.
KOK04556.
PhylomeDBQ9WVS6.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

CleanExMM_PARK2.
GenevestigatorQ9WVS6.

Family and domain databases

InterProIPR003977. Parkin.
IPR000626. Ubiquitin-like.
IPR029071. Ubiquitin-rel_dom.
IPR002867. Znf_C6HC.
[Graphical view]
PfamPF01485. IBR. 2 hits.
PF00240. ubiquitin. 1 hit.
[Graphical view]
PIRSFPIRSF037880. Parkin. 1 hit.
PRINTSPR01475. PARKIN.
SMARTSM00647. IBR. 2 hits.
SM00213. UBQ. 1 hit.
[Graphical view]
SUPFAMSSF54236. SSF54236. 1 hit.
PROSITEPS50053. UBIQUITIN_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ9WVS6.
NextBio307835.
PROQ9WVS6.
SOURCESearch...

Entry information

Entry namePRKN2_MOUSE
AccessionPrimary (citable) accession number: Q9WVS6
Secondary accession number(s): Q2KHJ9, Q9ES22, Q9ES23
Entry history
Integrated into UniProtKB/Swiss-Prot: October 11, 2004
Last sequence update: November 1, 1999
Last modified: June 11, 2014
This is version 115 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot