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  3. PARK2

PARK2 (Parkin RBR E3 ubiquitin protein ligase)

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The Function of PARK2

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, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2 (PubMed:10973942, PubMed:10888878, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:16135753, PubMed:21376232, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951). 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 (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11590439, PubMed:11431533, PubMed:19229105, PubMed:11590439, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (PubMed:25621951). 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 (PubMed:21376232). 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 (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.

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Protein names

Recommended name:

E3 ubiquitin-protein ligase parkin

Alternative name(s):

Parkin
Parkinson juvenile disease protein 2
Parkinson disease protein 2

PARK2 SNPs

    To see your genotype, you should be logged in and have a file with your genotype uploaded.

  1. RS12207186 (PARK2) ??
  2. RS13191362 (PARK2) ??
  3. RS16892673 (PARK2) ??
  4. RS1801334 (PARK2) ??
  5. RS3016539 (PARK2) ??
  6. RS4708928 (PARK2) ??
  7. RS7769089 (PARK2) ??
  8. RS926849 (PARK2) ??
  9. RS992037 (PARK2) ??

Top Gene-Substance Interactions

PARK2 Interacts with These Diseases

Disease Score

Substances That Increase PARK2

Substances Interaction Organism Category

Substances That Decrease PARK2

Substances Interaction Organism Category

Advanced Summary

     ovarian cancer Genetics Home Reference provides information about ovarian cancer. Parkinson disease Researchers have identified more than 200 PARK2 gene mutations that cause Parkinson disease, a condition characterized by progressive problems with movement and balance. Mutations in this gene are associated with the juvenile form of Parkinson disease, which appears before age 20, and some cases of the more common, late-onset form that begins after age 50. Some PARK2 gene mutations lead to an abnormally small parkin protein that is nonfunctional and is rapidly broken down (degraded) within cells. Other mutations insert, delete, or change DNA building blocks (nucleotides) in the PARK2 gene, leading to a defective version of the parkin protein or preventing the production of this protein. The PARK2 gene mutations associated with Parkinson disease usually lead to a loss of parkin activity. It is unclear how PARK2 gene mutations cause Parkinson disease. The loss of parkin activity probably disturbs the ubiquitin-proteasome system, which allows unneeded proteins to accumulate. A buildup of these proteins could disrupt normal cell activities such as the supply and release of synaptic vesicles, particularly those that contain a chemical messenger called dopamine. As parkin is normally abundant in the brain, its loss could lead to the impairment or death of nerve cells, including those that produce dopamine. Loss of dopamine-producing nerve cells is a characteristic feature of Parkinson disease. Mutations in the PARK2 gene may also disrupt the regulation of mitochondria. Researchers speculate that mitochondrial dysfunction in dopamine-producing nerve cells may play an important role in causing the signs and symptoms of Parkinson disease. cancers The PARK2 gene spans part of a region on chromosome 6 known as FRA6E. This region is known as a fragile area because it is unstable and prone to breakage and rearrangement. Changes involving the FRA6E region have been reported in several forms of human cancer, including glioblastoma (a form of brain cancer), colorectal cancer, lung cancer, and ovarian cancer. In some of these cancerous tumors, segments of the FRA6E region, including part or all of the PARK2 gene, are abnormally deleted or duplicated. These genetic changes are described as somatic because they occur only in tumor cells and are not inherited. As a result of these alterations, parkin activity is reduced or absent in these cells. Because parkin is thought to act as a tumor suppressor, a shortage of this protein's function could allow cells to grow and divide in an uncontrolled manner, leading to tumor formation. other disorders Studies suggest that common variations (polymorphisms) in the PARK2 gene (and a neighboring gene called PACRG) can increase the risk of contracting Hansen disease, also known as leprosy. This disease affects the nerves and skin and is caused by the bacterium Mycobacterium leprae. It remains unclear how PARK2 polymorphisms increase susceptibility to Hansen disease. Researchers believe that the ubiquitin-proteasome system may play a role in controlling infection. Polymorphisms in the PARK2 gene may subtly alter parkin's function, making the ubiquitin-proteasome system less efficient.

     The PARK2 gene, one of the largest human genes, provides instructions for making a protein called parkin. Parkin plays a role in the cell machinery that breaks down (degrades) unneeded proteins by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to move unneeded proteins into specialized cell structures known as proteasomes, where the proteins are degraded. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the availability of proteins that are involved in several critical cell activities, such as the timing of cell division and growth. Because of its activity in the ubiquitin-proteasome system, parkin belongs to a group of proteins called E3 ubiquitin ligases. Parkin appears to be involved in the maintenance of mitochondria, the energy-producing centers in cells. However, little is known about its role in mitochondrial function. Research suggests that parkin may help trigger the destruction of mitochondria that are not working properly. Studies of the structure and activity of parkin have led researchers to propose several additional activities for this protein. Parkin may act as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Parkin may also regulate the supply and release of sacs called synaptic vesicles from nerve cells. Synaptic vesicles contain chemical messengers that transmit signals from one nerve cell to another.

Conditions with Increased Gene Activity

Condition Change (log2fold) Comparison Species Experimental variables Experiment name

Conditions with Decreased Gene Activity

Condition Change (log2fold) Comparison Species Experimental variables Experiment name

Technical

The following transcription factors affect gene expression:

  • NF-kappaB
  • GR
  • GR-alpha
  • GR-beta
  • NF-kappaB1
  • STAT1
  • STAT1beta
  • STAT1alpha
  • STAT4

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).

Gene Pathways:

  • Immune System
  • Protein processing in endoplasmic reticulum
  • Parkinson's disease
  • Ubiquitin mediated proteolysis

Enzyme Regulation:

In the autoinhibited state the side chain of Phe-463 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-431, whereas the REP repressor element binds RING-1 and blocks its E2-binding site (PubMed:23727886, PubMed:23770887). Activation of PARK2 requires 2 steps: (1) phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated ubiquitin, leading to unlock repression of the catalytic Cys-431 by the RING-0 region via an allosteric mechanism and converting PARK2 to its fully-active form (PubMed:24660806, PubMed:24784582, PubMed:25527291). According to another report, phosphorylation at Ser-65 by PINK1 is not essential for activation and only binding to phosphorylated ubiquitin is essential to unlock repression (PubMed:24751536).

Molecular Function:

  • Transcription Regulatory Region Sequence-Specific Dna Binding
  • G-Protein Coupled Receptor Binding
  • Transcription Factor Activity, Sequence-Specific Dna Binding
  • Actin Binding
  • Ubiquitin-Protein Transferase Activity
  • Beta-Catenin Binding
  • Zinc Ion Binding
  • Tubulin Binding
  • Ligase Activity
  • Sh3 Domain Binding
  • Enzyme Binding
  • Kinase Binding
  • Protein Kinase Binding
  • Pdz Domain Binding
  • Hsp70 Protein Binding
  • Heat Shock Protein Binding
  • Ubiquitin Conjugating Enzyme Binding
  • Ubiquitin Protein Ligase Binding
  • Identical Protein Binding
  • Histone Deacetylase Binding
  • Ubiquitin Binding
  • Phospholipase Binding
  • Chaperone Binding
  • Ubiquitin Protein Ligase Activity
  • Cullin Family Protein Binding
  • Ubiquitin Protein Ligase Activity Involved In Erad Pathway
  • Ubiquitin-Specific Protease Binding
  • F-Box Domain Binding

Biological Processes:

  • Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
  • Protein Polyubiquitination
  • Mitochondrial Fission
  • Mitophagy
  • Negative Regulation Of Protein Phosphorylation
  • Startle Response
  • Transcription, Dna-Templated
  • Protein Monoubiquitination
  • Response To Oxidative Stress
  • Mitochondrion Organization
  • Central Nervous System Development
  • Learning
  • Adult Locomotory Behavior
  • Proteasomal Protein Catabolic Process
  • Regulation Of Autophagy
  • Positive Regulation Of Gene Expression
  • Negative Regulation Of Gene Expression
  • Positive Regulation Of Mitochondrial Fusion
  • Negative Regulation Of Mitochondrial Fusion
  • Regulation Of Mitochondrion Organization
  • Regulation Of Glucose Metabolic Process
  • Free Ubiquitin Chain Polymerization
  • Regulation Of Dopamine Secretion
  • Macroautophagy
  • Protein Ubiquitination
  • Regulation Of Protein Stability
  • Regulation Of Protein Ubiquitination
  • Protein Destabilization
  • Negative Regulation Of Actin Filament Bundle Assembly
  • Regulation Of Lipid Transport
  • Positive Regulation Of Proteasomal Ubiquitin-Dependent Protein Catabolic Process
  • Negative Regulation Of Glucokinase Activity
  • Cellular Response To Unfolded Protein
  • Response To Endoplasmic Reticulum Stress
  • Synaptic Transmission, Glutamatergic
  • Protein K29-Linked Ubiquitination
  • Erad Pathway
  • Regulation Of Dopamine Metabolic Process
  • Norepinephrine Metabolic Process
  • Dopamine Metabolic Process
  • Protein Ubiquitination Involved In Ubiquitin-Dependent Protein Catabolic Process
  • Positive Regulation Of I-Kappab Kinase/Nf-Kappab Signaling
  • Proteasome-Mediated Ubiquitin-Dependent Protein Catabolic Process
  • Positive Regulation Of Dna Binding
  • Negative Regulation Of Neuron Apoptotic Process
  • Cellular Protein Catabolic Process
  • Cellular Protein Metabolic Process
  • Protein K27-Linked Ubiquitination
  • Negative Regulation By Host Of Viral Genome Replication
  • Positive Regulation Of Protein Catabolic Process
  • Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
  • Negative Regulation Of Jnk Cascade
  • Negative Regulation Of Insulin Secretion
  • Protein Stabilization
  • Positive Regulation Of Neurotransmitter Uptake
  • Dopamine Uptake Involved In Synaptic Transmission
  • Protein Autoubiquitination
  • Regulation Of Mitochondrial Membrane Potential
  • Zinc Ion Homeostasis
  • Negative Regulation Of Cell Death
  • Regulation Of Canonical Wnt Signaling Pathway
  • Parkin-Mediated Mitophagy In Response To Mitochondrial Depolarization
  • Neuron Cellular Homeostasis
  • Protein K63-Linked Ubiquitination
  • Protein Localization To Mitochondrion
  • Aggresome Assembly
  • Protein K48-Linked Ubiquitination
  • Protein K11-Linked Ubiquitination
  • Cellular Response To Manganese Ion
  • Protein K6-Linked Ubiquitination
  • Negative Regulation Of Canonical Wnt Signaling Pathway
  • Positive Regulation Of Mitochondrial Fission
  • Negative Regulation Of Release Of Cytochrome C From Mitochondria
  • Cellular Response To Toxic Substance
  • Mitophagy In Response To Mitochondrial Depolarization
  • Mitochondrion To Lysosome Transport
  • Regulation Of Cellular Response To Oxidative Stress
  • Negative Regulation Of Neuron Death
  • Positive Regulation Of Proteasomal Protein Catabolic Process
  • Negative Regulation Of Endoplasmic Reticulum Stress-Induced Intrinsic Apoptotic Signaling Pathway
  • Negative Regulation Of Intrinsic Apoptotic Signaling Pathway By P53 Class Mediator
  • Negative Regulation Of Primary Amine Oxidase Activity
  • Positive Regulation Of Protein Linear Polyubiquitination
  • Regulation Of Synaptic Vesicle Transport
  • Negative Regulation Of Oxidative Stress-Induced Cell Death
  • Regulation Of Protein Targeting To Mitochondrion
  • Positive Regulation Of Tumor Necrosis Factor-Mediated Signaling Pathway
  • Cellular Response To Dopamine
  • Negative Regulation Of Oxidative Stress-Induced Neuron Intrinsic Apoptotic Signaling Pathway
  • Positive Regulation Of Oxidative Stress-Induced Neuron Intrinsic Apoptotic Signaling Pathway
  • Negative Regulation Of Endoplasmic Reticulum Stress-Induced Neuron Intrinsic Apoptotic Signaling Pathway
  • Negative Regulation Of Exosomal Secretion
  • Positive Regulation Of Dendrite Extension
  • Negative Regulation Of Spontaneous Neurotransmitter Secretion
  • Positive Regulation Of Retrograde Transport, Endosome To Golgi
  • Negative Regulation Of Intralumenal Vesicle Formation
  • Positive Regulation Of Protein Localization To Membrane
  • Regulation Of Reactive Oxygen Species Metabolic Process
  • Negative Regulation Of Reactive Oxygen Species Metabolic Process
*synonyms

Synonyms/Aliases/Alternative Names of the Gene:

hypothetical protein| park2| parkin| AR-JP| AS27_01208| AS28_08041| CB1_000390032| D623_10010737| E3 ubiquitin-protein ligase parkin| I79_009801| LPRS2| M959_02390| MDA_GLEAN10018878| N301_16777| N302_14545| N303_01146| N305_12077| N306_11141| N307_03724| N308_04117| N311_11461| N336_01666| PAL_GLEAN10013226| PANDA_009464| Park| parkin protein| Parkinson disease (autosomal recessive, juvenile) 2, parkin| parkinson juvenile disease protein 2| parkinson protein 2 E3 ubiquitin protein ligase| parkinson protein 2, E3 ubiquitin protein ligase| parkinson protein 2, E3 ubiquitin protein ligase (parkin)| parkin variant SV11bINS| parkin variant SV5DEL| PDJ| pdr-1| PRKN| TREES_T100014091| UY3_12545| Y1Q_011168| Y956_02990

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