Reviewed, UniProtKB/Swiss-Prot O60260 (PRKN2_HUMAN)

Names and origin

Protein names

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 names

Name:	PARK2
Synonyms:	PRKN

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	465 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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. These substrates include SYT11, CCNE1, GPR37, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP and SEPT5. May play a more general role in the ubiquitin proteasomal pathway by participating in the removal and/or detoxification of abnormally folded or damaged protein. 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.
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. 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.
Subcellular location	Cytoplasm. Nucleus. Note= Co-localizes with SYT11 in neutrites. Co-localizes with SNCAIP in brainstem Lewy bodies.
Tissue specificity	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.
Domain	The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes.
Post-translational modification	Auto-ubiquitinates in an E2-dependent manner leading to its own 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.
Involvement in disease	Defects in PARK2 are a cause of Parkinson disease (PD) [MIM:168600]. PD is a complex, multifactorial disorder that typically manifests after the age of 50 years, although early-onset cases (before 50 years) are known. PD generally arises as a sporadic condition but is occasionally inherited as a simple mendelian trait. Although sporadic and familial PD are very similar, inherited forms of the disease usually begin at earlier ages and are associated with atypical clinical features. PD is characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology of PD 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. Defects in PARK2 are the cause of autosomal recessive early onset Parkinson disease 2 (PARK2) [MIM:600116]; also known as early-onset parkinsonism with diurnal fluctuation (EPDF) or autosomal recessive juvenile Parkinson disease (PDJ). PARK2 is symptomatically different in several aspects from idiopathic Parkinson disease, although classic symptoms such as bradykinesia, rigidity and tremor are present. Additional clinical features include early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. PARK2 is usually characterized by onset before 40, with a mean age at onset of 23.2 years. Pathologically, PARK2 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. Defects in PARK2 may be involved in the development and/or progression of ovarian cancer.
Miscellaneous	The parkin locus (PRKN), adjacent to the 6q telomere is hyper-recombinable and lies within FRA6E, the third most common fragile site in tumor tissue.
Sequence similarities	Contains 2 IBR-type zinc fingers. Contains 2 RING-type zinc fingers. Contains 1 ubiquitin-like domain.
Caution	Has been said to contain 2 RING fingers, but these are not found by any domain detection methods.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Parkinson disease Parkinsonism
Domain	Repeat Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase
PTM	S-nitrosylation Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	central nervous system development Ref.1 Traceable author statement. Source: ProtInc protein ubiquitination during ubiquitin-dependent protein catabolic process Inferred from direct assay. Source: UniProtKB
Cellular component	Golgi apparatus Inferred from direct assay. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-KW perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB
Molecular function	protein binding Ref.11 Ref.22 Ref.23 Inferred from physical interaction. Source: UniProtKB ubiquitin-protein ligase activity Ref.8 Inferred from direct assay. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RANBP2	P49792	6	EBI-716346,EBI-973138

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O60260-1)

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: O60260-2)

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

Isoform 3 (identifier: O60260-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-79: Missing.
     291-297: AGCPNSL → VCLLPGM
     298-465: Missing.

Isoform 4 (identifier: O60260-4)

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

Isoform 5 (identifier: O60260-5)

The sequence of this isoform differs from the canonical sequence as follows:
     290-290: V → VGTGDTVVLRGALGGFRRGV
     362-368: FAFCREC → YGQRRTK
     369-465: 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_0000058576

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; atypical

Region

204 – 238

35

SYT11 binding 1

Region

257 – 293

37

SYT11 binding 2

Natural variations

Alternative sequence

1 – 191

191

Missing in isoform 4.

VSP_011705

Alternative sequence

1 – 79

79

Missing in isoform 3.

VSP_011706

Alternative sequence

179 – 206

28

Missing in isoform 2.

VSP_011707

Alternative sequence

290

1

V → VGTGDTVVLRGALGGFRRGV in isoform 5.

VSP_011708

Alternative sequence

291 – 297

7

AGCPNSL → VCLLPGM in isoform 3.

VSP_011709

Alternative sequence

298 – 465

168

Missing in isoform 3.

VSP_011710

Alternative sequence

362 – 368

7

FAFCREC → YGQRRTK in isoform 5.

VSP_011711

Alternative sequence

369 – 465

97

Missing in isoform 5.

VSP_011712

Natural variant

15

1

V → M in PD.

VAR_019733

Natural variant

33

1

R → Q in PD.

VAR_019734

Natural variant

37

1

P → L in PARK2.

VAR_019735

Natural variant

42

1

R → P in PD; early-onset; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding.

VAR_019736

Natural variant

46

1

A → P in PD; early-onset; sporadic.

VAR_019737

Natural variant

82

1

A → E in PARK2 and PD.

VAR_019738

Natural variant

92

1

A → V in PARK2.

VAR_019739

Natural variant

100

1

Q → H

VAR_019740

Natural variant

161

1

K → N in PARK2 and PD.

VAR_019741

Natural variant

167

1

S → N: dbSNP rs1801474.

VAR_019742

Natural variant

192

1

M → V in PD; early and late onset. dbSNP rs9456735.

VAR_019743

Natural variant

211

1

K → N in PD; early and late onset.

VAR_019744

Natural variant

211

1

K → R in PD; early onset.

VAR_019745

Natural variant

212

1

C → Y in PARK2.

VAR_019746

Natural variant

240

1

T → M in PD; late onset.

VAR_019747

Natural variant

240

1

T → R in PARK2; impairs the ability to ubiquitinate SNCAIP; loss of UBE2L3 binding.

VAR_019748

Natural variant

253

1

C → Y in PD; late onset.

VAR_019749

Natural variant

256

1

R → C in PARK2 and PD; early and late onset; impairs the ability to ubiquitinate SNCAIP. dbSNP rs34424986.

VAR_019750

Natural variant

271

1

R → S

VAR_019751

Natural variant

275

1

R → W in PARK2 and PD; early and late onset; impairs the ability to ubiquitinate SNCAIP.

VAR_019752

Natural variant

280

1

D → N in PD.

VAR_019753

Natural variant

284

1

G → R in PARK2.

VAR_019754

Natural variant

289

1

C → G in PD; fails to ubiquitinate SYT11; loses ability to bind SYT11.

VAR_019755

Natural variant

328

1

G → E in PD.

VAR_019756

Natural variant

334

1

R → C in PD.

VAR_019757

Natural variant

339

1

A → S

VAR_019758

Natural variant

351

1

T → P in PARK2; impairs folding of IBR domain.

VAR_019759

Natural variant

366

1

R → W

VAR_019760

Natural variant

380

1

V → L: dbSNP rs1801582.

VAR_019761

Natural variant

394

1

D → N: dbSNP rs1801334.

VAR_019762

Natural variant

415

1

T → N in PARK2 and PD; impairs the ability to ubiquitinate SNCAIP; does not affect turnover of CDCRE1.

VAR_019763

Natural variant

430

1

G → D in PD; early onset.

VAR_019764

Natural variant

431

1

C → F in PARK2.

VAR_019765

Natural variant

437

1

P → L in PD; early and late onset.

VAR_019766

Natural variant

441

1

C → R in PD.

VAR_019767

Experimental info

Mutagenesis

332

1

C → S: Impairs folding of IBR domain

Mutagenesis

337

1

C → A: Impairs the ability to ubiquitinate SNCAIP

Mutagenesis

365

1

C → S: Impairs protein folding

Mutagenesis

418

1

C → R: Fails to ubiquitinate SYT11. Does not loose ability to bind SYT11

Mutagenesis

421

1

C → A: Impairs the ability to ubiquitinate SNCAIP

Mutagenesis

431

1

C → A: Impairs the ability to ubiquitinate SNCAIP

Sequence conflict

223

1

S → P Ref.1 Ref.2

Sequence conflict

289 – 290

2

CV → MI in AAM21461. Ref.2

Sequence conflict

339

1

A → V Ref.5

Secondary structure

1

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465

Helix Strand Turn

Details...

Beta strand

2 – 7

6

Turn

8 – 10

3

Beta strand

11 – 17

7

Beta strand

19 – 21

3

Helix

23 – 33

11

Beta strand

38 – 45

8

Beta strand

48 – 50

3

Turn

52 – 55

4

Helix

57 – 60

4

Beta strand

63 – 70

8

Beta strand

318 – 320

3

Beta strand

334 – 336

3

Beta strand

354 – 356

3

Turn

366 – 369

4

Beta strand

377 – 379

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 17, 2006. Version 2. Checksum: 9A8BB802A3FC84C3	FASTA	465	51,641
	10 20 30 40 50 60 MIVFVRFNSS HGFPVEVDSD TSIFQLKEVV AKRQGVPADQ LRVIFAGKEL RNDWTVQNCD 70 80 90 100 110 120 LDQQSIVHIV QRPWRKGQEM NATGGDDPRN AAGGCEREPQ SLTRVDLSSS VLPGDSVGLA 130 140 150 160 170 180 VILHTDSRKD SPPAGSPAGR SIYNSFYVYC KGPCQRVQPG KLRVQCSTCR QATLTLTQGP 190