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Symbol PRKN contributors: mct/ - updated : 26-02-2016
HGNC name parkinson protein 2, E3 ubiquitin protein ligase (parkin)
HGNC id 8607
Corresponding disease
PARK2 Parkinson disease 2, juvenile
Location 6q26      Physical location : -
Synonym name
  • E3 ubiquitin ligase
  • parkin 2
  • parkin
  • Synonym symbol(s) ARJP, PDJ, LPRS2, parkin, PARK2
    EC.number 6.3.2.-
    TYPE functioning gene
    SPECIAL FEATURE head to head, opposite orientation
    text head to head and downstream PACRG
    STRUCTURE 1380.25 kb     12 Exon(s)
    regulatory sequence Promoter
    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 - D6S253 - D6S305 - qter
    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
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivepharynx   highly
    Hearing/Equilibriumear   highly
    Reproductivemale systemtestis   
     male systemprostate   
    Respiratoryrespiratory tractlarynx  highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    cell lineage
    cell lines
    at STAGE
  • 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
    interspecies homolog to murine Park2 (83.8pc)
    homolog to rattus Park2 (85.6pc)
  • E3 ubiquitin ligase family
  • RBR family
  • parkin subfamily
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
  • 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)
  • moves to mitochondria with low membrane potential, thereby activating the latent enzymatic activity of the protein, which in turn triggers Parkin-mediated ubiquitylation of numerous mitochondrial substrates
  • mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism
  • PARK2 translocation to mitochondria was enhanced by BH3-only proteins or a BH3-only mimetic
  • 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
  • PRKN and PINK1 are regulated by neddylation and impaired NEDD8 modification of these proteins likely contributes to Parkinson disease pathogenesis
  • protects against apoptosis, reduces BAX at the mitochondria, and mediates the ubiquitination of BAX
  • prevents stress-induced accumulation of BAX at the mitochondria
  • is a ubiquitin-ligating enzyme (E3) that catalyzes ubiquitin transfer from ubiquitin-activating and -conjugating enzymes (E1/E2) to a substrate
  • MFN1, MFN2, PARK2 regulating mitochondrial spheroid formation and mitophagy that could represent different strategies of mitochondrial homeostatic response to oxidative stress
  • was required to promote the degradation of whole organelles by autophagy
  • role for the HSPA1A-PARK2 axis in the regulation of muscle insulin sensitivity
  • acts as a master regulator of the stability of G1/S cyclins and functions as the tumor suppressor mediating the coordination of different classes of cyclins
  • PINK1-dependent phosphorylation of both PARK2 and ubiquitin is sufficient for full activation of parkin E3 activity
  • PINK1 and PARK2, mediate local mitophagy of dysfunctional mitochondria in neuronal axons
  • plays a central role in many stress response pathways, and in particular, in mitochondrial quality control
  • DNM1L and PARK2/Parkin work likely in a synergistic manner to maintain mitochondrial function and structural integrity in the heart and brain
  • E3 ubiquitin ligases PARKIN and MUL1 play redundant roles in elimination of paternal mitochondria
  • PRKN tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death
  • CELLULAR PROCESS cell life, cell death/apoptosis
    protein, degradation
    protein, ubiquitin dependent proteolysis
    text neuronal cell without formation of Lewy bodies
  • by preventing mitochondrial movement, the PINK1/PARK2 pathway may quarantine damaged mitochondria prior to their clearance
  • role of PARL-PINK1-PRKN pathway in adipocyte differentiation
  • PINK1–PARK2 pathway in mitochondria is involved in mitochondrial fusion and fission
  • TOMM machinery is a key molecular switch in the mitochondrial clearance program controlled by the PINK1-PARK2 pathway
  • PINK1-PARK2-mediated pathway is required for local mitophagy in distal axons in response to focal damage
  • a component
  • PRKN and TARDBP formed a multiprotein complex with HDAC6, perhaps to mediate TARDBP translocation
    small molecule
  • 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
  • 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
  • HDAC6 directly binds to PARK2 and mediates its transport in response to proteasome inhibition
  • 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 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 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 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)
  • Ataxin-3 opposes PARK2 ubiquitination by regulating the E2 ubiquitin-conjugating enzyme
  • PRKN and PINK1 are NEDD8 conjugated
  • PARK2 prevented basal and apoptotic stress-induced translocation of BAX to the mitochondria
  • PINK1 autophosphorylation upon membrane potential dissipation is essential for PARK2 recruitment to damaged mitochondria
  • VDAC1, VDAC2, VDAC3 serve as mitochondrial docking sites to recruit PRKN from the cytosol to defective mitochondria
  • mitochondrial hexokinase I (HK1) is a novel PRKN substrate
  • PRKN-mediated HK1 degradation may inhibit glycolysis, and consequently Parkin’s mitochondriallocalization is hindered, suggesting HK1 functions as a negative feedback component
  • PARK2 ubiquitinates TARDBP and facilitates its cytosolic accumulation through a multiprotein complex with HDAC6
  • UBE2A is a regulator of PRKN-dependent mitophagy suggesting a critical role for UBE2A in maintaining neuronal function
  • PRKN differently regulates PSEN1 and PSEN2 functions by direct control of their promoter transcription
  • NACC1 and PRKN are co-localized within the cell and interact with one another, leading to a decrease in PRKN levels
  • interaction of cytosolic PINK1 with PARK2 represses PARK2 translocation to the mitochondria and subsequent mitophagy
  • PARK2 ubiquitination affects its protein stability and E3 ligase activity, possibly leading to SNCA sequestration and subsequent clearance
  • RHOT1 is a direct PRKN substrate
  • PINK1 acts as an upstream factor for PARK2 and is essential both for the activation of latent E3 PARK2 activity and for recruiting PARK2 onto depolarized mitochondria
  • BECN1 interacts with the Parkinson disease-related protein PARK2 (BECN1 interacts with PARK2 and regulates PARK2 translocation to mitochondria as well as PARK2-induced mitophagy prior to autophagosome formation)
  • UBE2N, UBE2L3 and UBE2D2/3 synergistically contribute to PRKN-mediated mitophagy
  • BCL2 proteins suppressed mitophagy through inhibition of PARK2 translocation to depolarized mitochondria
  • USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for PARK2-mediated mitophagy
  • PINK1 accumulation leads to PARK2 recruitment from the cytosol, which in turn promotes the degradation of the damaged mitochondria by autophagy (mitophagy)
  • BNIP3L is a substrate of PRKN to drive PRKN-mediated mitophagy, and promoting mitophagy in the PINK1/PRKN pathway associated with Parkinson Disease pathogenesis
  • degradation of wildtype and mutant ATXN2 is dependent on FBXW8, and ATXN2 accumulation selectively modulates FBXW8 levels, while PARK2 might act indirectly through FBXW8
  • transiently interacts with PINK1, and IMMT downregulation leads to a reduction in PINK1 and mislocalization of PRKN
  • PRKN modulates mitochondrial depolarization and apoptosis in a BCL2L1-dependent manner
  • PGAM5 regulates PINK1-PRKN-mediated mitophagy, which can exert a neuroprotective effect against carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced apoptosis
  • PRKN recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MARCH5
  • cell & other
    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)
    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
    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 (
    constitutional     --low  
    in chronic obstructive pulmonary disease (COPD) lung, suggesting that insufficient mitophagy is a part of the pathogenic sequence of COPD
    tumoral     --low  
    crucial involvement of parkin deficiency in the pathogenesis of pancreatic cancer
  • to leprosy
  • to late-onset form of Parkinson disease
  • to type 2 diabetes patients with nephropathy
  • to familial lung cancer
  • 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
  • c.823C>T (p.Arg275Trp) associated to familial lung cancer
  • Candidate gene
    Therapy target
  • Park2 heterozygous knockout mice with ApcMin mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity