5oat | pdb_00005oat
PINK1 structure
Structural highlights
FunctionPINK1_TRICA Acts as a serine/threonine-protein kinase (PubMed:25474007, PubMed:26784449, PubMed:29475881, PubMed:32484300, PubMed:28980524, PubMed:24751536, PubMed:26116755, PubMed:29991771). Exhibits a substrate preference for proline at position P+1 and a general preference at several residues for basic residues such as arginine (PubMed:22645651). Also exhibits moderate preferences for a phosphotyrosine at position P-3 and a tryptophan at P-5 (PubMed:22645651). Critical to mitochondrial homeostasis it mediates several pathways that maintain mitochondrial health and function (By similarity). Protects against mitochondrial dysfunction during cellular stress by phosphorylating mitochondrial proteins such as park and likely Drp1, to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:25474007, PubMed:32484300, PubMed:28980524, PubMed:24751536, PubMed:26116755, PubMed:29991771). 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). Mediates the translocation and activation of park at the outer membrane (OMM) of dysfunctional/depolarized mitochondria (PubMed:25474007, PubMed:26116755). At the OMM of damaged mitochondria, phosphorylates pre-existing polyubiquitin chains, the Pink1-phosphorylated polyubiquitin then recruits park from the cytosol to the OMM where park is fully activated by phosphorylation at 'Ser-80' by Pink1 (PubMed:24751536, PubMed:25474007, PubMed:29475881, PubMed:26116755, PubMed:29991771). When cellular stress results in irreversible mitochondrial damage, functions with park to promote the clearance of dysfunctional and/or depolarized mitochondria by selective autophagy (mitophagy) (By similarity). The Pink1-park pathway also promotes fission and/or inhibits fusion of damaged mitochondria, by phosphorylating and thus promoting the park-dependent degradation of proteins involved in mitochondrial fusion/fission such as Marf, Opa1 and fzo (By similarity). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (By similarity). Also likely to promote mitochondrial fission independently of park and Atg7-mediated mitophagy, via the phosphorylation and activation of Drp1 (PubMed:32484300). 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 by promoting the park-dependent ubiquitination of transcriptional repressor Paris which leads to its subsequent proteasomal degradation and allows activation of the transcription factor srl (By similarity). Functions with park to promote 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). During oogenesis, phosphorylates and inactivates larp on the membrane of defective mitochondria, thus impairing local translation and mtDNA replication and consequently, reducing transmission of deleterious mtDNA mutations to the mature oocyte (By similarity). Phosphorylates the mitochondrial acyl-CoA dehydrogenase Mcad, and appears to be important for maintaining fatty acid and amino acid metabolism via a mechanism that is independent of it's role in maintaining production of ATP (By similarity). Exhibits a substrate preference for proline at position P+1 and a general preference at several residues for basic residues such as arginine (PubMed:22645651). Also exhibits moderate preferences for a phosphotyrosine at position P-3 and a tryptophan at P-5 (PubMed:22645651).[UniProtKB:Q0KHV6][1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedMutations in the human kinase PINK1 (hPINK1) are associated with autosomal recessive early-onset Parkinson's disease (PD). hPINK1 activates Parkin E3 ligase activity, involving phosphorylation of ubiquitin and the Parkin ubiquitin-like (Ubl) domain via as yet poorly understood mechanisms. hPINK1 is unusual amongst kinases due to the presence of three loop insertions of unknown function. We report the structure of Tribolium castaneum PINK1 (TcPINK1), revealing several unique extensions to the canonical protein kinase fold. The third insertion, together with autophosphorylation at residue Ser205, contributes to formation of a bowl-shaped binding site for ubiquitin. We also define a novel structural element within the second insertion that is held together by a distal loop that is critical for TcPINK1 activity. The structure of TcPINK1 explains how PD-linked mutations that lie within the kinase domain result in hPINK1 loss-of-function and provides a platform for the exploration of small molecule modulators of hPINK1. Structure of PINK1 and mechanisms of Parkinson's disease associated mutations.,Kumar A, Tamjar J, Waddell AD, Woodroof HI, Raimi OG, Shaw AM, Peggie M, Muqit MM, van Aalten DM Elife. 2017 Oct 5;6. pii: e29985. doi: 10.7554/eLife.29985. PMID:28980524[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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