Q9WVS6 (PRKN2_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 111. History...
Names and origin
|Protein names||Recommended name:|
E3 ubiquitin-protein ligase parkin
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||464 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
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.
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 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. Ref.7
Nucleus By similarity. Endoplasmic reticulum By similarity. Cytoplasm › cytosol Probable. Cell projection › dendrite By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Mitochondrion By similarity. Cell junction › synapse 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
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
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
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.
Auto-ubiquitinates in an E2-dependent manner leading to its own degradation By similarity. Also polyubiquitinated by RNF41 for proteasomal degradation By similarity.
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.
Contains 1 IBR-type zinc finger.
Contains 3 RING-type zinc fingers.
Contains 1 ubiquitin-like domain.
|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
|Isoform 3 (identifier: Q9WVS6-3) |
The sequence of this isoform differs from the canonical sequence as follows:
244-261: RSPVLVFQCNHRHVICLD → SHLPLSSGASVWTRPHLH
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 464||464||E3 ubiquitin-protein ligase parkin||PRO_0000058577|
|Domain||1 – 76||76||Ubiquitin-like|
|Zinc finger||140 – 224||85||RING-type 0; atypical|
|Zinc finger||237 – 292||56||RING-type 1; atypical|
|Zinc finger||312 – 376||65||IBR-type|
|Zinc finger||417 – 448||32||RING-type 2|
|Region||204 – 238||35||SYT11 binding 1|
|Region||257 – 293||37||SYT11 binding 2|
|Region||377 – 409||33||REP By similarity|
|Active site||430||1||By similarity|
|Alternative sequence||244 – 261||18||RSPVL…VICLD → SHLPLSSGASVWTRPHLH in isoform 3.||VSP_011713|
|Alternative sequence||245 – 254||10||SPVLVFQCNH → FMRMSKHRTS in isoform 2.||VSP_011714|
|Alternative sequence||255 – 464||210||Missing in isoform 2.||VSP_011715|
|Alternative sequence||262 – 464||203||Missing in isoform 3.||VSP_011716|
|Sequence conflict||137||1||P → PA Ref.1|
|Sequence conflict||137||1||P → PA in AAG13890. Ref.2|
Helix Strand Turn
|Beta strand||1 – 11||11|
|Beta strand||13 – 17||5|
|Helix||23 – 34||12|
|Helix||38 – 40||3|
|Beta strand||41 – 45||5|
|Beta strand||48 – 50||3|
|Helix||56 – 58||3|
|Beta strand||66 – 73||8|
|||"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.
|||"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.
|||"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).
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|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.
|RefSeq||NP_057903.1. NM_016694.3. |
3D structure databases
|SMR||Q9WVS6. Positions 1-76, 140-464. |
Protein-protein interaction databases
|BioGrid||206136. 17 interactions.|
|IntAct||Q9WVS6. 8 interactions.|
Protocols and materials databases
Genome annotation databases
|UCSC||uc008akk.1. mouse. |
|MGI||MGI:1355296. Park2. |
Enzyme and pathway databases
Gene expression databases
Family and domain databases
|InterPro||IPR003977. Parkin. |
|PANTHER||PTHR11685:SF2. PTHR11685:SF2. 1 hit. |
|Pfam||PF01485. IBR. 2 hits. |
PF00240. ubiquitin. 1 hit.
|PIRSF||PIRSF037880. Parkin. 1 hit. |
|PRINTS||PR01475. PARKIN. |
|SMART||SM00647. IBR. 2 hits. |
SM00213. UBQ. 1 hit.
|PROSITE||PS50053. UBIQUITIN_2. 1 hit. |
|Accession||Primary (citable) accession number: Q9WVS6|
Secondary accession number(s): Q2KHJ9, Q9ES22, Q9ES23
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|