InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: PARK2

Summary

InnateDB Protein

IDBP-98840.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

PARK2

Protein Name

parkinson protein 2, E3 ubiquitin protein ligase (parkin)

Synonyms

AR-JP; LPRS2; PDJ; PRKN;

Species

Homo sapiens

Ensembl Protein

ENSP00000355860

InnateDB Gene

IDBG-98830 (PARK2)

Protein Structure

UniProt Annotation

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, RHOT1/MIRO1, MFN1, MFN2, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, TOMM20, USP30, 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) by the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:24896179). 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. {ECO:0000269PubMed:10888878, ECO:0000269PubMed:10973942, ECO:0000269PubMed:12628165, ECO:0000269PubMed:12719539, ECO:0000269PubMed:15105460, ECO:0000269PubMed:15728840, ECO:0000269PubMed:16135753, ECO:0000269PubMed:17846173, ECO:0000269PubMed:18541373, ECO:0000269PubMed:19029340, ECO:0000269PubMed:19801972, ECO:0000269PubMed:19966284, ECO:0000269PubMed:20889974, ECO:0000269PubMed:21376232, ECO:0000269PubMed:21532592, ECO:0000269PubMed:22082830, ECO:0000269PubMed:23620051, ECO:0000269PubMed:23754282, ECO:0000269PubMed:23933751, ECO:0000269PubMed:24784582, ECO:0000269PubMed:24896179}.

Subcellular Localization

Cytoplasm, cytosol. Nucleus. Endoplasmic reticulum. Mitochondrion. Note=Mainly localizes in the cytosol. Co-localizes with SYT11 in neutrites. Co-localizes with SNCAIP in brainstem Lewy bodies. Mitochondrial localization gradually increases with cellular growth. Also relocates to dysfunctional mitochondria that have lost the mitochondrial membrane potential; recruitment to mitochondria is PINK1-dependent.

Disease Associations

Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease 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. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269PubMed:12629236, ECO:0000269PubMed:12730996}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996 and PubMed:12629236).Parkinson disease 2 (PARK2) [MIM:600116]: A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA- induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, 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. {ECO:0000269PubMed:10072423, ECO:0000269PubMed:10824074, ECO:0000269PubMed:10939576, ECO:0000269PubMed:11163284, ECO:0000269PubMed:11179010, ECO:0000269PubMed:11487568, ECO:0000269PubMed:11971093, ECO:0000269PubMed:12056932, ECO:0000269PubMed:12112109, ECO:0000269PubMed:12114481, ECO:0000269PubMed:12116199, ECO:0000269PubMed:12362318, ECO:0000269PubMed:12397156, ECO:0000269PubMed:12629236, ECO:0000269PubMed:12730996, ECO:0000269PubMed:15584030, ECO:0000269PubMed:22956510, ECO:0000269PubMed:9560156, ECO:0000269PubMed:9731209}. Note=The disease is caused by mutations affecting the gene represented in this entry.Note=Defects in PARK2 may be involved in the development and/or progression of ovarian cancer.

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. Found in serum (at protein level). {ECO:0000269PubMed:19501131}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 456 experimentally validated interaction(s) in this database.
They are also associated with 19 interaction(s) predicted by orthology.

Experimentally validated
Total	456 [view]
Protein-Protein	453 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	3 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	19 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004842	ubiquitin-protein transferase activity
GO:0005515	protein binding
GO:0008270	zinc ion binding
GO:0016874	ligase activity
GO:0019900	kinase binding
GO:0019901	protein kinase binding
GO:0030165	PDZ domain binding
GO:0031625	ubiquitin protein ligase binding
GO:0042802	identical protein binding
GO:0043130	ubiquitin binding
GO:0051087	chaperone binding
GO:0061630	ubiquitin protein ligase activity
GO:1990381	ubiquitin-specific protease binding

Biological Process

GO:0000209	protein polyubiquitination
GO:0000422	mitochondrion degradation
GO:0001933	negative regulation of protein phosphorylation
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006511	ubiquitin-dependent protein catabolic process
GO:0006513	protein monoubiquitination
GO:0007417	central nervous system development
GO:0008219	cell death
GO:0010506	regulation of autophagy
GO:0016567	protein ubiquitination
GO:0032232	negative regulation of actin filament bundle assembly
GO:0033132	negative regulation of glucokinase activity
GO:0042787	protein ubiquitination involved in ubiquitin-dependent protein catabolic process
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0043524	negative regulation of neuron apoptotic process
GO:0044257	cellular protein catabolic process
GO:0045087	innate immune response (InnateDB)
GO:0046676	negative regulation of insulin secretion
GO:0051865	protein autoubiquitination
GO:0060548	negative regulation of cell death
GO:0070534	protein K63-linked ubiquitination
GO:0070842	aggresome assembly
GO:0070936	protein K48-linked ubiquitination
GO:0070997	neuron death
GO:0090201	negative regulation of release of cytochrome c from mitochondria
GO:1901215	negative regulation of neuron death
GO:2000377	regulation of reactive oxygen species metabolic process

Cellular Component

GO:0000151	ubiquitin ligase complex
GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005783	endoplasmic reticulum
GO:0005794	Golgi apparatus
GO:0005829	cytosol
GO:0016235	aggresome
GO:0048471	perinuclear region of cytoplasm