5caw
Structure of Pediculus humanus Parkin bound to phospho-ubiquitin
Structural highlights
FunctionPRKN_PEDHC E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes in the form of a thioester and then directly transfers the ubiquitin to targeted substrates, such as Marf, Opa1, Sep1, Tom20 and porin (By similarity). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates, depending on the context (PubMed:26161729). Protects against mitochondrial dysfunction during cellular stress, by acting downstream of Pink1, to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (By similarity). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (By similarity). Appears to be particularly important in maintaining the physiology and function of cells with high energy demands that are undergoing stress or altered metabolic environment, including spermatids, muscle cells and neurons such as the dopaminergic (DA) neurons (By similarity). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires Pink1-mediated phosphorylation of both park and ubiquitin (By similarity). In depolarized mitochondria, mediates the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of porin/VDAC; polyubiquitination of porin promotes mitophagy, while monoubiquitination of porin decreases mitochondrial calcium influx which ultimately inhibits apoptosis (By similarity). When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins (By similarity). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (By similarity). In developing tissues, inhibits JNK-mediated apoptosis by negatively regulating bsk transcription (By similarity). The Pink1-park pathway also promotes fission and/or inhibits fusion of damaged mitochondria by mediating the ubiquitination and subsequent degradation of proteins involved in mitochondrial fusion/fission such as Marf and Opa1 (By similarity). This prevents the refusion of unhealthy mitochondria with the healthy mitochondrial network and/or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (By similarity). Regulates motility of damaged mitochondria by phosphorylating Miro which likely promotes its park-dependent degradation by the proteasome; in motor neurons, this inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria being eliminated in the soma (By similarity). The Pink1-park pathway is also involved in mitochondrial regeneration processes such as promoting mitochondrial biogenesis, activating localized mitochondrial repair, promoting selective turnover of mitochondrial proteins and initiating the mitochondrial import of endogenous proteins (By similarity). Involved in mitochondrial biogenesis via the ubiquitination of transcriptional repressor Paris which leads to its subsequent proteasomal degradation and allows activation of the transcription factor srl (By similarity). Promotes localized mitochondrial repair by activating the translation of specific nuclear-encoded mitochondrial RNAs (nc-mtRNAs) on the mitochondrial surface, including several key electron transport chain component nc-mtRNAs (By similarity).[UniProtKB:Q7KTX7][1] Publication Abstract from PubMedThe E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1 (encoded by PARK6) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy. PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin as well as the PARKIN ubiquitin-like (Ubl) domain. These phosphorylation events lead to PARKIN recruitment, and activation by an unknown allosteric mechanism. Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators. Mechanism of phospho-ubiquitin-induced PARKIN activation.,Wauer T, Simicek M, Schubert A, Komander D Nature. 2015 Jul 10. doi: 10.1038/nature14879. PMID:26161729[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. 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