The precise function of<unk> 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<unk> on's disease known as autosomal recessive juvenile<unk> on's disease (AR-JP). Moreover,<unk> is described to be necessary for mitophagy (autophagy of mitochondria). However, how loss of function of the<unk> protein leads to dopaminergic cell death in this disease is unclear. The prevailing hypothesis is that<unk> helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of<unk> include synphilin-1, CDC-rel1, cyclin E, p38 tRNA synthase, Pael-R, synaptotagmin XI, sp22 and<unk> itself (see also ubiquitin ligase). Additionally,<unk> contains a C-terminal motif that binds PDZ domains.<unk> has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK and PICK1. A. Schematic diagram delineating arrangement of<unk> functional domains. B. Cartoon representation of<unk> in its autoinhibited state, with the catalytic cysteine in RING2 occluded by RING0 while Ubl and REP linker prevents E2 from binding to RING1. RING0, RING1, IBR and RING2 each coordinate two Zn ions (approximate location denoted by grey circles) for structural stability, leading to a stoichiometry of 8 Zn2+/parkin. Like other members of the RING-between-RING (RBR) family of E3 ligases,<unk> 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<unk> activation.<unk> 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<unk> 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<unk> 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.<unk> 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<unk> recruitment to damaged mitochondria. PINK1 also phosphorylates Ub at Ser65, accelerating its discharge from E2 and enhancing its affinity for<unk>  Although structural changes following phosphorylation are uncertain, crystallisation of<unk> 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<unk> and that its hydrophobic interface with RING1 buries Cys431 in inactive<unk>  targeting of phosphorylated Ub and/or Ubl towards this binding niche might be critical in dismantling autoinhibitory complexes during<unk> activation.
Parkin 
Peripherin
CEPP
Tetraspanin
Dystrophin
Alpha-synuclein
Huntingtin-interacting protein 1
MSin3 interaction domain