Parkin is a protein which in humans is encoded by the PARK2 gene.
 The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation.
Mutations in this gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP).
Moreover, Parkin is described to be necessary for mitophagy (autophagy of mitochondria).

However, how loss of function of the parkin protein leads to dopaminergic cell death in this disease is unclear.
The prevailing hypothesis is that parkin helps degrade one or more proteins toxic to dopaminergic neurons.
 Putative substrates of parkin include synphilin-1, CDC-rel1, cyclin E, p38 tRNA synthase, Pael-R, synaptotagmin XI, sp22 and parkin itself (see also ubiquitin ligase).
Additionally, Parkin contains a C-terminal motif that binds PDZ domains.
Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK and PICK1.

Like other members of the RING-between-RING (RBR) family of E3 ligases, parkin possesses two RING finger domains and an in-between-RING (IBR) region.
RING1 forms the binding site for E2 Ub-conjugating enzyme while RING2 contains the catalytic cysteine residue (Cys431) that cleaves Ub off E2 and transiently binds it to E3 via a thioester bond.
Ub transfer is aided by neighbouring residues histidine His433, which accepts a proton from Cys431 to activate it, and glutamate Glu444, which is involved in autoubiquitination.
Together these form the catalytic triad, whose assembly is required for parkin activation.
Parkin also contains an N-terminal Ub-like domain (Ubl) for specific substrate recognition, a unique RING0 domain and a repressor (REP) region that tonically suppresses ligase activity.

Under resting conditions, the tightly coiled conformation of parkin renders it inactive, as access to the catalytic RING2 residue is sterically blocked by RING0, while the E2 binding domain on RING1 is occluded by Ubl and REP.
Activating stimuli disrupt these interdomain interactions and induce parkin to collapse along the RING1-RING0 interface.
The active site of RING2 is drawn towards E2-Ub bound to RING1, facilitating formation of the Ub-thioester intermediate.
Parkin activation requires phosphorylation of serine Ser65 in Ubl by serine/threonine kinase, PINK1.
Addition of a charged phosphate destabilises hydrophobic interactions between Ubl and neighbouring subregions, reducing autoinhibitory effects of this N-terminus domain.
Ser65Ala missense mutations were found to ablate Ub-parkin binding whilst inhibiting parkin recruitment to damaged mitochondria.
PINK1 also phosphorylates Ub at Ser65, accelerating its discharge from E2 and enhancing its affinity for parkin.

Although structural changes following phosphorylation are uncertain, crystallisation of parkin revealed a cationic pocket in RING0 formed by lysine and arginine residues Lys161, Arg163 and Lys211 that forms a putative phosphate binding site.
Considering that RING0 is unique to parkin and that its hydrophobic interface with RING1 buries Cys431 in inactive parkin, targeting of phosphorylated Ub and/or Ubl towards this binding niche might be critical in dismantling autoinhibitory complexes during parkin activation.
Parkin is a protein which in humans is encoded by the PARK2 gene.  The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Mutations in this gene are known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP). Moreover, Parkin is described to be necessary for mitophagy (autophagy of mitochondria).
However, how loss of function of the parkin protein leads to dopaminergic cell death in this disease is unclear. The prevailing hypothesis is that parkin helps degrade one or more proteins toxic to dopaminergic neurons.  Putative substrates of parkin include synphilin-1, CDC-rel1, cyclin E, p38 tRNA synthase, Pael-R, synaptotagmin XI, sp22 and parkin itself (see also ubiquitin ligase). Additionally, Parkin contains a C-terminal motif that binds PDZ domains. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK and PICK1.
Like other members of the RING-between-RING (RBR) family of E3 ligases, parkin possesses two RING finger domains and an in-between-RING (IBR) region. RING1 forms the binding site for E2 Ub-conjugating enzyme while RING2 contains the catalytic cysteine residue (Cys431) that cleaves Ub off E2 and transiently binds it to E3 via a thioester bond. Ub transfer is aided by neighbouring residues histidine His433, which accepts a proton from Cys431 to activate it, and glutamate Glu444, which is involved in autoubiquitination. Together these form the catalytic triad, whose assembly is required for parkin activation. Parkin also contains an N-terminal Ub-like domain (Ubl) for specific substrate recognition, a unique RING0 domain and a repressor (REP) region that tonically suppresses ligase activity.
Under resting conditions, the tightly coiled conformation of parkin renders it inactive, as access to the catalytic RING2 residue is sterically blocked by RING0, while the E2 binding domain on RING1 is occluded by Ubl and REP. Activating stimuli disrupt these interdomain interactions and induce parkin to collapse along the RING1-RING0 interface. The active site of RING2 is drawn towards E2-Ub bound to RING1, facilitating formation of the Ub-thioester intermediate. Parkin activation requires phosphorylation of serine Ser65 in Ubl by serine/threonine kinase, PINK1. Addition of a charged phosphate destabilises hydrophobic interactions between Ubl and neighbouring subregions, reducing autoinhibitory effects of this N-terminus domain. Ser65Ala missense mutations were found to ablate Ub-parkin binding whilst inhibiting parkin recruitment to damaged mitochondria. PINK1 also phosphorylates Ub at Ser65, accelerating its discharge from E2 and enhancing its affinity for parkin.
Although structural changes following phosphorylation are uncertain, crystallisation of parkin revealed a cationic pocket in RING0 formed by lysine and arginine residues Lys161, Arg163 and Lys211 that forms a putative phosphate binding site. Considering that RING0 is unique to parkin and that its hydrophobic interface with RING1 buries Cys431 in inactive parkin, targeting of phosphorylated Ub and/or Ubl towards this binding niche might be critical in dismantling autoinhibitory complexes during parkin activation.
Parkin (ligase)