8uyi

Structural highlights

Function

PINK1_PEDHC Acts as a serine/threonine-protein kinase (PubMed:22645651, PubMed:26161729, PubMed:29160309). Exhibits a substrate preference for proline at position P+1 and a general preference at several residues for basic residues such as arginine (By similarity). Also exhibits moderate preferences for a phosphotyrosine at position P-3 and a tryptophan at P-5 (By similarity). 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:26161729). 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:26161729). 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-94' by Pink1 (By similarity). 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 (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 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).[UniProtKB:D6WMX4][UniProtKB:Q0KHV6]^{[1] [2] [3]}

References

1. ↑ Woodroof HI, Pogson JH, Begley M, Cantley LC, Deak M, Campbell DG, van Aalten DM, Whitworth AJ, Alessi DR, Muqit MM. Discovery of catalytically active orthologues of the Parkinson's disease kinase PINK1: analysis of substrate specificity and impact of mutations. Open Biol. 2011 Nov;1(3):110012. PMID:22645651 doi:10.1098/rsob.110012
2. ↑ Wauer T, Simicek M, Schubert A, Komander D. Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature. 2015 Jul 10. doi: 10.1038/nature14879. PMID:26161729 doi:http://dx.doi.org/10.1038/nature14879
3. ↑ Schubert AF, Gladkova C, Pardon E, Wagstaff JL, Freund SMV, Steyaert J, Maslen SL, Komander D. Structure of PINK1 in complex with its substrate ubiquitin. Nature. 2017 Oct 30. pii: nature24645. doi: 10.1038/nature24645. PMID:29160309 doi:http://dx.doi.org/10.1038/nature24645
4. ↑ Gan ZY, Callegari S, Nguyen TN, Kirk NS, Leis A, Lazarou M, Dewson G, Komander D. Interaction of PINK1 with nucleotides and kinetin. Sci Adv. 2024 Jan 19;10(3):eadj7408. PMID:38241364 doi:10.1126/sciadv.adj7408