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FLASH GENE
Symbol PARK2 contributors: mct/ - updated : 11-02-2011
HGNC name parkinson protein 2, E3 ubiquitin protein ligase (parkin)
HGNC id 8607
Corresponding disease
PARK2 Parkinson disease 2, juvenile
Location 6q26      Physical location : 161.768.590 - 163.148.834
Synonym name
  • E3 ubiquitin ligase
  • parkin 2
  • parkin
  • Synonym symbol(s) ARJP, PDJ, PRKN, LPRS2, parkin
    EC.number 6.3.2.-
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head, opposite orientation
    text head to head and downstream PACRG
    STRUCTURE 1380.25 kb     12 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    Binding site   transcription factor   HRE
    text structure a bifunctional promoter common with PACRG with homology to the alpha-synuclein promoter
  • several putative cis-elements for various tanscription factors
  • TP53 REs in promoter region and intron 1 predicated by the p53MH algorithm
  • MAPPING cloned Y linked N status provisional
    Map cen - D6S1579 - D6S1358 - PARK2 PARK2 - D6S253 - D6S305 - qter
    Physical map
    TAGAP 6q25.3 T-cell activation GTPase activating protein LOC389441 6 LOC389441 LOC389442 6 LOC389442 LOC389443 6 LOC389443 LOC389444 6 similar to frazzled CG8581-PA FNDC1 6q25 fibronectin type III domain containing 1 LOC389445 6 similar to 60S ribosomal protein L21 SOD2 6q25.2 superoxide dismutase 2, mitochondrial WTAP 6q25-q27 Wilms tumor 1 associated protein ACAT2 6q25.3-q26 acetyl-Coenzyme A acetyltransferase 2 (acetoacetyl Coenzyme A thiolase) TCP1 6q25.1-q25.2 t-complex 1 MRPL18 6q25.3 mitochondrial ribosomal protein L18 PNLDC1 6q25.3 poly(A)-specific ribonuclease (PARN)-like domain containing 1 MAS1 6q25.3-q26 MAS1 oncogene IGF2R 6q26-q27 insulin-like growth factor 2 receptor SLC22A1 6q27 solute carrier family 22 (organic cation transporter), member 1 SLC22A2 6q26-q27 solute carrier family 22 (organic cation transporter), member 2 SLC22A3 6q26-q27 solute carrier family 22 (extraneuronal monoamine transporter), member 3 APOAL 6q26-q27 apolipoprotein A-like LPA 6q26-q27 lipoprotein, Lp(a) PLG 6q26 plasminogen LOC389446 6 similar to apolipoprotein(a) (EC 3.4.21.-) - rhesus macaque (fragment) LOC389447 6 LOC389447 MAP3K4 6q25.3 mitogen-activated protein kinase kinase kinase 4 AGPAT4 6q25.3 1-acylglycerol-3-phosphate O-acyltransferase 4 (lysophosphatidic acid acyltransferase, delta) C6orf59 6q25.3 chromosome 6 open reading frame 59 PARK2 6q25.2-q27 Parkinson disease (autosomal recessive, juvenile) 2, parkin PACRG 6q26 PARK2 co-regulated QKI 6q26-27 quaking homolog, KH domain RNA binding (mouse)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 4073 - 465 - 1997 9042918
    isoform 1
    11 splicing 3989 - 437 - 1997 9042918
    isoform 2
    9 splicing 3626 - 316 leukocytes 1997 9042918
    isoform 3
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestivepharynx   highly
    Hearing/Equilibriumear   highly
    Reproductivemale systemtestis   
     male systemprostate   
    Respiratoryrespiratory tractlarynx  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an ubiquitin-like domain at its N terminus
  • a Zn2+ binding domain
  • a Sh2-like domain
  • a linker region and a ubiquitin-like domain at the N-terminus
  • an IBR domain that augment binding of the E2 proteins UBCH7 and UBCH8, and the subsequent ubiquitination of the proteins synphilin-1, SEPT5, and SIM2
  • two RING finger domains separated by an in-between-ring domain at its C terminus
  • HOMOLOGY
    interspecies homolog to murine Park2 (83.8pc)
    homolog to rattus Park2 (85.6pc)
    Homologene
    FAMILY
  • E3 ubiquitin ligase family
  • RBR family
  • parkin subfamily
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,outer
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    text
  • centriolar
  • within the mitochondrial organelle of proliferating cells, but in the cytosol and Golgi in brain tissues
  • translocating to uncoupled mitochondria to induce their autophagy
  • dominantly located in cytosol, whereas it is also located in mitochondria
  • upon mitochondrial damage, translocates to mitochondria to mediate their selective elimination by autophagic degradation
  • translocates from the cytosol to depolarized mitochondria and induces their autophagic removal (mitophagy)
  • basic FUNCTION
  • involved in the protein degradation as a ubiquitin-protein ligase (E3 activity) collaborating with UBE2L3
  • may be promoting the degradation of substrates localized in mitochondria and involved in the late mitochondrial phase of ceramide-mediated cell-death
  • ubiquitinating SYT11 and regulating the turn-over of SYT11
  • playing an important role for aggresome formation in neuronal cells
  • promoting the degradation of the synaptic vesicle-associated protein PNUTL1 (CDCREL1)
  • involved in the regulation of mitochondrial transcription/replication other than the ubiquitin-mediated protein degradation system in proliferating cells
  • suppresses MAO expression (and may limit the production of reactive oxygen species generated by MAO in dopamine oxidation and would, thus, be beneficial to the survival of dopaminergic neurons)
  • functions as an autophagy inhibitory protein via its interaction with Beclin 1, and the autophagy level maintained by BCL2 is compatible with cell survival, rather than cell death
  • activates signaling through the IkappaB kinase (IKK)/nuclear factor kappaB (NF-kappaB) pathway
  • modulating the expression of KIF11 through the Hsp70-JNK-c-Jun signaling pathway
  • promotes DNA repair and protects against genotoxicity, (potential pathogenic mechanism in Parkinson disease)
  • involved in the cellular homeastasis of a series of proteins by modulating their ubiquitylation and thereby controlling their subsequent degradation by the proteasome
  • regulates PINK1 stabilization via direct interaction with PINK1, and operates through a common pathway with PINK1 in the pathogenesis of early-onset Parkinson disease
  • playing a role in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress
  • involved in regulation of Wnt signaling and may protects dopaminergic neurons against excessive Wnt signaling and CTNNB-induced cell death
  • ubiquitin ligase-independent function of parkin in the control of transcription and a functional link between parkin and TP53 that is altered by PARK2 mutations
  • together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy
  • tumor suppressor gene whose haploinsufficiency cooperates with mutant APC in colorectal carcinogenesis
  • with PINK1 are intimately involved in preventing mitochondrial dysfunction
  • mono-ubiquitinates BCL2 and regulates autophagy via BCL2
  • Parkin, but not its E3 ligase-deficient mutants, mono-ubiquitinates BCL2 to stabilize it, resulting in an increase of its binding to Beclin 1, thereby repressing autophagy in normal conditions or starvation
  • PINK1 and PARK2 are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to Parkinson disease pathogenesis
  • restoration of autophagy in PINK1-silenced cells by PARK2 reverses ATP synthesis inhibition and the ubiquitination of MFN1 and MFN2 play a role in PINK1/PARK2-mediated mitophagy
  • PARK2 and EIF4E act in a common pathway, likely modulating cap-dependent translation initiation events
  • PARK7 works in parallel to the PINK1/PARK2 pathway to maintain mitochondrial function in the presence of an oxidative environment
  • promotes MDM2-arrestin interaction but inhibits arrestin ubiquitination, and parkin mutations differentially affect the stimulation of MDM2 binding
  • has a potential role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson disease
  • regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome- and mitophagy-dependent pathways
  • could be a key factor that regulates cellular homeostasis through mitochondrial turnover in both an autophagy-dependent and a proteasome-dependent manner
  • ARIH1 and PARK2 functioning via a HECT-like mechanism whereby RING1 harbours the E2-binding site and RING2 harbours the active-site cysteine
  • involved in ubiquitination of AMBRA1
  • CELLULAR PROCESS cell life, cell death/apoptosis
    protein, degradation
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    text neuronal cell without formation of Lewy bodies
    PATHWAY
    metabolism
    signaling
  • by preventing mitochondrial movement, the PINK1/PARK2 pathway may quarantine damaged mitochondria prior to their clearance
  • a component
  • PINK1–PARK2 pathway in mitochondria is involved in mitochondrial fusion and fission
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • ubiquitin conjugating enzyme (E2) dependent and SNCA (synuclein alpha) (ubiquination of ASP22) with GPR37 (PAELR)
  • interacts with programmed cell death-2 isoform 1 (PDCD2-1) and promotes its ubiquitination
  • interacting with PSMA4, through the the C-terminal IBR-RING domain of parkin and the C-terminal part of PSMA4
  • SYT11
  • PARK7 promoted by oxidative stress
  • CDCREL1
  • associating with PFAM
  • interacting with SCNAIP1 (ubiquitination of synphilin-1 by parkin may be involved in the formation of Lewy body inclusions associated with Parkinson disease)
  • interacts with and promotes degradation-independent ubiquitylation of IKKgamma/NEMO (NF-kappaB essential modifier) and TRAF2, two critical components of the NF-kappaB pathway
  • cell-type dependent functional interaction between PARK2 and LIMK1 (links parkin and LIMK1 in the pathogenesis of familial PD)
  • interacting with PINK1 (phosphorylation by PINK1 on its linker region promotes its mitochondrial translocation, and the RING1 domain of Parkin is critical for this occurrence)
  • directly interacts with PINK1, but did not bind to pathogenic PINK1 mutants (stabilizes PINK1 by interfering with its degradation via the ubiquitin-mediated proteasomal pathway)
  • interacting with PINK1 (PARK7, PINK1, and PARK2 function in common biological processes that are critical for mitochondrial function, such that compromise of their activity leads to human disease)
  • interacting wiuth RNF41 which catalyze degradation of PARK2 via the ubiquitin-proteasome pathway, suggesting that it may be involved in the development of Parkinson disease via the regulation of PARK2
  • interacting with ABL1 (ABL1 SH3 domain is required for the interaction with parkin)
  • BCL2 anti-apoptotic and autophagy inhibitory protein, is a substrate for parkin (directly interacts with BCL2 specifically through its C terminus and mediates the mono-ubiquitination of BCL2)
  • functional interaction between ATXN3 and PARK2 (both wild-type and polyQ-expanded mutant ataxin-3 can deubiquitinate parkin, regardless of the lysine residue used to assemble poly-Ub chains) (
  • PARK2 suppresses the transcription of MAOA, MAOB to control oxidative stress induced by dopamine oxidation
  • after mitochondrial fission upon depolarization, prevents or delays refusion of mitochondria, likely by the elimination of mitofusins (MFN1, MFN2)
  • ZNF746 is a parkin (PARK2) interacting substrate (parkin regulates the levels of PARIS via the ubiquitin proteasome system (UPS))
  • HSPA9 interacting with PARK2 (relatively decreased mortalin expression level and its impaired interaction with PARK2 could affect its roles in mitochondrial function)
  • interacts with and selectively mediates the atypical poly-ubiquitination of MFN1, leading to its enhanced turnover by proteasomal degradation
  • interaction with AMBRA1 (interaction of Parkin with AMBRA1 is a key mechanism for induction of the final clearance step of Parkin-mediated mitophagy)
  • contributes to the functions of TP53 in regulating energy metabolism, and antioxidant defense, and thus the function of TP53 in tumor suppression
  • C1QBP is a novel interactor of parkin in the brain (C1QBP can regulate mitochondrial morphology and dynamics by promoting parkin degradation through autophagy) (PMID;
  • Ataxin-3 opposes PARK2 ubiquitination by regulating the E2 ubiquitin-conjugating enzyme
  • cell & other
    REGULATION
    activated by S-nitrosylation
    stress-induced upregulation of parkin is mediated by ATF4
    inhibited by ABL1 (tyrosine phosphorylation by ABL1 is a major posttranslational modification that inhibits parkin function, possibly contributing to pathogenesis of sporadic Parkinson disease)
    repressed by dopamine (principal transmitter lost in Parkinson disease)
    ASSOCIATED DISORDERS
    corresponding disease(s) PARK2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in breast and ovarian carcinoma
    constitutional     --over  
    involved in reducing aggresome formation and Lewy bodies but can be dissociated from effect on neuronal survival
    tumoral        
    significantly associated with adenomatous polyposis coli (APC) deficiency in colorectal cancer
    tumoral     --low  
    dramatically down-regulated in a variety of breast cancer cell lines as well as in primary breast cancer tissues
    constitutional     --other  
    increased turnover of parkin may contribute to the pathogenesis of Machado-Joseph diseas and help explain some of its parkinsonian features (
    Susceptibility
  • to leprosy
  • to late-onset form of Parkinson disease
  • to type 2 diabetes patients with nephropathy
  • Variant & Polymorphism SNP
  • increasing the susceptibility to leprosy
  • maybe due to heterozygous mutations especially in exon 7, and influenced by environmental and intrinsic factors V
  • in late-onset form of Parkinson disease
  • SNP increasing the risk of type 2 diabetes patients with nephropathy
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Park2 heterozygous knockout mice with ApcMin mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity