E3 ubiquitin-protein ligase parkin - Mus musculus (Mouse)

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Q9WVS6 (PRKN2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified May 1, 2013. Version 104. History...

Clusters with 100%, 90%, 50% identity |

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Names·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase parkin
EC=6.3.2.-

Gene names

Name:	Park2
Synonyms:	Prkn

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

Protein attributes

Sequence length	464 AA.
Sequence status	Complete.
Protein existence	Evidence 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 of SNCAIP, 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. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). Loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2. 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. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene By similarity. Ref.5
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 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) By similarity. Interacts with PSMA7 and RNF41 By similarity. Interacts with PINK1 By similarity.
Subcellular location	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
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.
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.
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 2 RING-type zinc fingers. Contains 1 ubiquitin-like domain.

Ontologies

Keywords
Biological process	Autophagy Ubl conjugation pathway
Cellular component	Cell junction Cell membrane Cell projection Cytoplasm Endoplasmic reticulum Membrane Mitochondrion Nucleus Postsynaptic cell membrane Synapse
Coding sequence diversity	Alternative splicing
Domain	Repeat Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase
PTM	S-nitrosylation Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	adult locomotory behavior Inferred from mutant phenotype PubMed 18346797. Source: MGI autophagy Inferred from electronic annotation. Source: UniProtKB-KW 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 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 monoubiquitination 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 startle response Inferred from mutant phenotype PubMed 15249681. Source: MGI synaptic transmission, glutamatergic Inferred from mutant phenotype PubMed 12915482. Source: MGI ubiquitin-dependent protein catabolic process Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from sequence or structural similarity. Source: UniProtKB 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 electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW 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_function	ubiquitin-protein ligase activity Inferred from direct assay PubMed 20064468. Source: MGI zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ranbp2	Q9ERU9	2	EBI-973635,EBI-643756
Znf746	Q3U133	2	EBI-973635,EBI-3862590

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 464

464

E3 ubiquitin-protein ligase parkin

PRO_0000058577

Regions

Domain

1 – 76

Ubiquitin-like

Zinc finger

237 – 292

RING-type 1; atypical

Zinc finger

312 – 376

IBR-type

Zinc finger

417 – 448

RING-type 2

Region

204 – 238

SYT11 binding 1

Region

257 – 293

SYT11 binding 2

Natural variations

Alternative sequence

244 – 261

RSPVL…VICLD → SHLPLSSGASVWTRPHLH in isoform 3.

VSP_011713

Alternative sequence

245 – 254

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

Experimental info

Sequence conflict

137

P → PA Ref.1

Sequence conflict

137

P → PA in AAG13890. Ref.2

Secondary structure

464

Helix Strand Turn

Details...

Sequences

Sequence		Length	Mass (Da)
Isoform 1 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: 5574A285A9A1B080 Show »	FASTA	464	51,618
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 »	FASTA	254	28,084
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 TDVRFMRMSK HRTS « Hide
Isoform 3 [UniParc]. Checksum: 6DA482E28FE80671 Show »	FASTA	261	28,629
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 TDVSHLPLSS GASVWTRPHL H « Hide

References

	« Hide 'large scale' referencesShow '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]	"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.

IPI

IPI00126445.
IPI00471131.
IPI00471132.

RefSeq

NP_057903.1. NM_016694.3.

UniGene

Mm.311110.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1MG8	NMR	-	A	1-76	[»]
2ZEQ	X-ray	1.65	A	1-76	[»]
3B1L	X-ray	1.85	X	1-76	[»]

ProteinModelPortal

Q9WVS6.

SMR

Q9WVS6. Positions 1-76, 306-383, 410-463.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9WVS6. 2 interactions.

MINT

MINT-2736580.

STRING

10090.ENSMUSP00000063644.

PTM databases

PhosphoSite

Q9WVS6.

Proteomic databases

PRIDE

Q9WVS6.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

50873.

KEGG

mmu:50873.

UCSC

uc008akj.1. mouse.
uc008akk.1. mouse.

Organism-specific databases

CTD

5071.

MGI

MGI:1355296. Park2.

Phylogenomic databases

eggNOG

NOG278133.

HOGENOM

HOG000013184.

HOVERGEN

HBG053682.

InParanoid

Q2KHJ9.

K04556.

OrthoDB

EOG4HHP2G.

Enzyme and pathway databases

UniPathway

UPA00143.

Gene expression databases

CleanEx

MM_PARK2.

Genevestigator

Q9WVS6.

GermOnline

ENSMUSG00000023826. Mus musculus.

Family and domain databases

InterPro

IPR003977. Parkin.
IPR000626. Ubiquitin.
IPR019955. Ubiquitin_supergroup.
IPR002867. Znf_C6HC.
[Graphical view]

PANTHER

PTHR11685:SF2. PTHR11685:SF2. 1 hit.

Pfam

PF01485. IBR. 2 hits.
PF00240. ubiquitin. 1 hit.
[Graphical view]

PIRSF

PIRSF037880. Parkin. 1 hit.

PRINTS

PR01475. PARKIN.

SMART

SM00647. IBR. 2 hits.
SM00213. UBQ. 1 hit.
[Graphical view]

PROSITE

PS00299. UBIQUITIN_1. False negative.
PS50053. UBIQUITIN_2. 1 hit.
PS00518. ZF_RING_1. False negative.
PS50089. ZF_RING_2. False negative.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q9WVS6.

NextBio

307835.

SOURCE

Search...

Entry information

Entry name

PRKN2_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 104 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

MGD cross-references

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

PATHWAY comments

Index of metabolic and biosynthesis pathways

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Natural variations

Experimental info

Secondary structure

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents