Q9JK66 (PRKN2_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Gene names

Name:	Park2
Synonyms:	Prkn

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	465 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.
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 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 By similarity. Ref.5
Subcellular location	Nucleus By similarity. Endoplasmic reticulum By similarity. Cytoplasm › cytosol By similarity. 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 By similarity. Relocates to dysfunctional mitochondria that have lost the mitochondial membrane potential; recruitement to mitochondria is PINK1-dependent By similarity.
Tissue specificity	Largely confined to neuronal elements, including fibers and neuropil. Highly expressed at the forebrain level, in pyramidal cells of layer V, in various cortical regions and cerebellum. Expressed in the nucleus of diagonal band of Broca, nucleus basalis, bed nucleus of the stria terminalis, and olfactory tubercle. Moderate expression is seen in most neurons of the subthalamic nucleus, heart, skeletal muscle and testis. Moderate expression was found in frontal cortex, parietal cortex, cerebellum, heart, skeletal muscle and testis. Ref.2
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. S-nitrosylated By similarity.
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	autophagy Inferred from electronic annotation. Source: UniProtKB-KW neuron death Inferred from sequence or structural similarity. Source: UniProtKB neuron maturation Inferred from expression pattern. Source: RGD 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 response to corticosterone stimulus Inferred from expression pattern. Source: RGD response to drug Inferred from expression pattern. Source: RGD response to unfolded protein Inferred from direct assay. Source: RGD ubiquitin-dependent protein catabolic process Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	Golgi membrane Inferred from direct assay. Source: RGD cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum Inferred from direct assay. Source: RGD membrane raft Inferred from direct assay. Source: RGD mitochondrion Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW postsynaptic density Inferred from direct assay. Source: RGD postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-KW synaptic vesicle Inferred from direct assay. Source: RGD
Molecular function	protein complex binding Inferred from direct assay. Source: RGD ubiquitin-protein ligase activity Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ranbp2	D4A054	2	EBI-973793,EBI-973937

Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9JK66-1)

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: Q9JK66-2)

The sequence of this isoform differs from the canonical sequence as follows:
     429-446: GGCMHMKCPQPQCKLEWC → ERMHVQYTMCIPGAHGGY
     447-465: Missing.

Isoform 3 (identifier: Q9JK66-3)

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

Isoform 4 (identifier: Q9JK66-4)

The sequence of this isoform differs from the canonical sequence as follows:
     57-57: Q → QHPQDGFCHKSHLAVHNLSQQDVTQ

Isoform 5 (identifier: Q9JK66-5)

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

Isoform 6 (identifier: Q9JK66-6)

The sequence of this isoform differs from the canonical sequence as follows:
     1-191: Missing.
     390-394: AYRVD → EDVCT
     395-465: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 465

465

E3 ubiquitin-protein ligase parkin

PRO_0000058578

Regions

Domain

1 – 76

76

Ubiquitin-like

Zinc finger

238 – 293

56

RING-type 1; atypical

Zinc finger

313 – 377

65

IBR-type

Zinc finger

418 – 449

32

RING-type 2

Region

204 – 238

35

SYT11 binding 1

Region

257 – 293

37

SYT11 binding 2

Natural variations

Alternative sequence

1 – 191

191

Missing in isoform 3 and isoform 6.

VSP_011717

Alternative sequence

57

1

Q → QHPQDGFCHKSHLAVHNLSQ QDVTQ in isoform 4.

VSP_011718

Alternative sequence

179 – 206

28

Missing in isoform 5.

VSP_011719

Alternative sequence

390 – 394

5

AYRVD → EDVCT in isoform 6.

VSP_011720

Alternative sequence

395 – 465

71

Missing in isoform 6.

VSP_011721

Alternative sequence

429 – 446

18

GGCMH…KLEWC → ERMHVQYTMCIPGAHGGY in isoform 2.

VSP_011722

Alternative sequence

447 – 465

19

Missing in isoform 2.

VSP_011723

Experimental info

Sequence conflict

24

1

F → C in AAF34874. Ref.1

Sequence conflict

138

1

E → A in BAA92431. Ref.3

Sequence conflict

348

1

K → R in BAA92431. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

465

Helix Strand Turn

Details...

Beta strand

2 – 9

8

Beta strand

14 – 16

3

Helix

23 – 33

11

Helix

38 – 40

3

Beta strand

41 – 44

4

Helix

56 – 58

3

Beta strand

65 – 71

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 2000. Version 1. Checksum: E13CF170AD6D042B	FASTA	465	51,709
	10 20 30 40 50 60 MIVFVRFNSS YGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL QNHLTVQNCD 70 80 90 100 110 120 LEQQSIVHIV QRPQRKSHET NASGGDKPQS TPEGSIWEPR SLTRVDLSSH ILPADSVGLA 130 140 150 160 170 180 VILDTDSKSD SEAARGPEAK PTYHSFFVYC KGPCHKVQPG KLRVQCGTCR QATLTLAQGP 190 200 210 220 230 240 SCWDDVLIPN RMSGECQSPD CPGTRAEFFF KCGAHPTSDK DTSVALNLIT NNSRSIPCIA 250 260 270 280 290 300 CTDVRNPVLV FQCNHRHVIC LDCFHLYCVT RLNDRQFVHD AQLGYSLPCV AGCPNSLIKE 310 320 330 340 350 360 LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEQGQKKV TCEGGNGLGC 370 380 390 400 410 420 GFVFCRDCKE AYHEGECDSM FEASGATSQA YRVDQRAAEQ ARWEEASKET IKKTTKPCPR 430 440 450 460 CNVPIEKNGG CMHMKCPQPQ CKLEWCWNCG CEWNRACMGD HWFDV
	Isoform 2 [UniParc]. Checksum: F06FAF788531DF5C	FASTA	446	49,368
	10 20 30 40 50 60 MIVFVRFNSS YGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL QNHLTVQNCD 70 80 90 100 110 120 LEQQSIVHIV QRPQRKSHET NASGGDKPQS TPEGSIWEPR SLTRVDLSSH ILPADSVGLA 130 140 150 160 170 180 VILDTDSKSD SEAARGPEAK PTYHSFFVYC KGPCHKVQPG KLRVQCGTCR QATLTLAQGP 190 200 210 220 230 240 SCWDDVLIPN RMSGECQSPD CPGTRAEFFF KCGAHPTSDK DTSVALNLIT NNSRSIPCIA 250 260 270 280 290 300 CTDVRNPVLV FQCNHRHVIC LDCFHLYCVT RLNDRQFVHD AQLGYSLPCV AGCPNSLIKE 310 320 330 340 350 360 LHHFRILGEE QYNRYQQYGA EECVLQMGGV LCPRPGCGAG LLPEQGQKKV TCEGGNGLGC 370 380 390 400 410 420 GFVFCRDCKE AYHEGECDSM FEASGATSQA YRVDQRAAEQ ARWEEASKET IKKTTKPCPR 430 440 CNVPIEKNER MHVQYTMCIP GAHGGY
	Isoform 3 [UniParc]. Checksum: B29BB58E86EB5DFE	FASTA	274	30,642
	10 20 30 40 50 60 MSGECQSPDC PGTRAEFFFK CGAHPTSDKD TSVALNLITN NSRSIPCIAC TDVRNPVLVF 70 80 90 100 110 120 QCNHRHVICL DCFHLYCVTR LNDRQFVHDA QLGYSLPCVA GCPNSLIKEL HHFRILGEEQ 130 140 150 160 170 180 YNRYQQYGAE ECVLQMGGVL CPRPGCGAGL LPEQGQKKVT CEGGNGLGCG FVFCRDCKEA 190 200 210 220 230 240 YHEGECDSMF EASGATSQAY RVDQRAAEQA RWEEASKETI KKTTKPCPRC NVPIEKNGGC 250 260 270 MHMKCPQPQC KLEWCWNCGC EWNRACMGDH WFDV
	Isoform 4 [UniParc]. Checksum: 49F53B8F358E2AB5	FASTA	489	54,418
	10 20 30 40 50 60 MIVFVRFNSS YGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL QNHLTVQHPQ 70 80 90 100 110 120 DGFCHKSHLA VHNLSQQDVT QNCDLEQQSI VHIVQRPQRK SHETNASGGD KPQSTPEGSI 130 140 150 160 170 180 WEPRSLTRVD LSSHILPADS VGLAVILDTD SKSDSEAARG PEAKPTYHSF FVYCKGPCHK 190 200 210 220 230 240 VQPGKLRVQC GTCRQATLTL AQGPSCWDDV LIPNRMSGEC QSPDCPGTRA EFFFKCGAHP 250 260 270 280 290 300 TSDKDTSVAL NLITNNSRSI PCIACTDVRN PVLVFQCNHR HVICLDCFHL YCVTRLNDRQ 310 320 330 340 350 360 FVHDAQLGYS LPCVAGCPNS LIKELHHFRI LGEEQYNRYQ QYGAEECVLQ MGGVLCPRPG 370 380 390 400 410 420 CGAGLLPEQG QKKVTCEGGN GLGCGFVFCR DCKEAYHEGE CDSMFEASGA TSQAYRVDQR 430 440 450 460 470 480 AAEQARWEEA SKETIKKTTK PCPRCNVPIE KNGGCMHMKC PQPQCKLEWC WNCGCEWNRA CMGDHWFDV
	Isoform 5 [UniParc]. Checksum: 3227286E41EBE5E3	FASTA	437	48,734
	10 20 30 40 50 60 MIVFVRFNSS YGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL QNHLTVQNCD 70 80 90 100 110 120 LEQQSIVHIV QRPQRKSHET NASGGDKPQS TPEGSIWEPR SLTRVDLSSH ILPADSVGLA 130 140 150 160 170 180 VILDTDSKSD SEAARGPEAK PTYHSFFVYC KGPCHKVQPG KLRVQCGTCR QATLTLAQEF 190 200 210 220 230 240 FFKCGAHPTS DKDTSVALNL ITNNSRSIPC IACTDVRNPV LVFQCNHRHV ICLDCFHLYC 250 260 270 280 290 300 VTRLNDRQFV HDAQLGYSLP CVAGCPNSLI KELHHFRILG EEQYNRYQQY GAEECVLQMG 310 320 330 340 350 360 GVLCPRPGCG AGLLPEQGQK KVTCEGGNGL GCGFVFCRDC KEAYHEGECD SMFEASGATS 370 380 390 400 410 420 QAYRVDQRAA EQARWEEASK ETIKKTTKPC PRCNVPIEKN GGCMHMKCPQ PQCKLEWCWN 430 CGCEWNRACM GDHWFDV
	Isoform 6 [UniParc]. Checksum: 3CFF551C49EB0783	FASTA	203	22,288
	10 20 30 40 50 60 MSGECQSPDC PGTRAEFFFK CGAHPTSDKD TSVALNLITN NSRSIPCIAC TDVRNPVLVF 70 80 90 100 110 120 QCNHRHVICL DCFHLYCVTR LNDRQFVHDA QLGYSLPCVA GCPNSLIKEL HHFRILGEEQ 130 140 150 160 170 180 YNRYQQYGAE ECVLQMGGVL CPRPGCGAGL LPEQGQKKVT CEGGNGLGCG FVFCRDCKEA 190 200 YHEGECDSMF EASGATSQED VCT

References

[1]	"Cloning and distribution of the rat parkin mRNA." D'Agata V., Zhao W., Cavallaro S. Brain Res. Mol. Brain Res. 75:345-349(2000) [PubMed: 10686358] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4; 5 AND 6). Strain: Sprague-Dawley.
[2]	"Cloning of rat parkin cDNA and distribution of parkin in rat brain." Gu W.-J., Abbas N., Lagunes M.Z., Parent A., Pradier L., Bohme G.A., Agid Y., Hirsch E.C., Raisman-Vozari R., Brice A. J. Neurochem. 74:1773-1776(2000) [PubMed: 10737637] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY. Tissue: Hypothalamus.
[3]	"The expression of parkin mRNA in developing, adult and ageing rat CNS." Hattori N., Wang M., Mizuno Y. Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Strain: Sprague-Dawley.
[4]	"Molecular cloning of rat Parkin gene." Soda M., Imai Y., Takahashi R. Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Strain: Sprague-Dawley. Tissue: Brain.
[5]	"Functional modulation of parkin through physical interaction with SUMO-1." Um J.W., Chung K.C. J. Neurosci. Res. 84:1543-1554(2006) [PubMed: 16955485] [Abstract] Cited for: INTERACTION WITH SUMO1.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF343574 mRNA. Translation: AAL73348.1.
AF381277 mRNA. Translation: AAM21452.1.
AF381278 mRNA. Translation: AAM21453.1.
AF381279 mRNA. Translation: AAM21454.1.
AF381280 mRNA. Translation: AAM21455.1.
AF381281 mRNA. Translation: AAM21456.1.
AF168004 mRNA. Translation: AAF34874.1.
AF210434 mRNA. Translation: AAG37013.1.
AF257234 mRNA. Translation: AAF68666.1.
AB039878 mRNA. Translation: BAA92431.1.

IPI

IPI00204126.
IPI00204131.
IPI00470231.
IPI00471482.
IPI00471483.
IPI00471486.

RefSeq

NP_064478.1. NM_020093.1.

UniGene

Rn.207194.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KNB	NMR	-	A	1-76	[»]

ProteinModelPortal

Q9JK66.

SMR

Q9JK66. Positions 307-384.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9JK66. 1 interaction.

MINT

MINT-220162.

STRING

Q9JK66.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

56816.

KEGG

rno:56816.

UCSC

AF381280. rat.

Organism-specific databases

CTD

5071.

RGD

61797. Park2.

Phylogenomic databases

eggNOG

roNOG14913.

GeneTree

ENSGT00390000011034.

HOVERGEN

HBG053682.

Gene expression databases

ArrayExpress

Q9JK66.

Genevestigator

Q9JK66.

GermOnline

ENSRNOG00000018013. Rattus norvegicus.

Family and domain databases

InterPro

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

KO

K04556.

PANTHER

PTHR11685:SF2. Parkin. 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

NextBio

611225.

Entry information

Entry name

PRKN2_RAT

Accession

Primary (citable) accession number: Q9JK66
Secondary accession number(s): Q8K5C3 , Q8K5C4, Q8K5C5, Q8K5C6, Q8VHY6, Q9JLL1, Q9JM64

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2004
Last sequence update:	October 1, 2000
Last modified:	November 16, 2011
This is version 83 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program