positive regulation of mitochondrial fission / autophagy / regulation of apoptotic process / mitochondrial outer membrane / mitochondrial inner membrane / non-specific serine/threonine protein kinase / protein kinase activity / phosphorylation / protein serine/threonine kinase activity / ATP binding ...positive regulation of mitochondrial fission / autophagy / regulation of apoptotic process / mitochondrial outer membrane / mitochondrial inner membrane / non-specific serine/threonine protein kinase / protein kinase activity / phosphorylation / protein serine/threonine kinase activity / ATP binding / metal ion binding / cytosol 類似検索 - 分子機能
Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性
National Health and Medical Research Council (NHMRC, Australia)
オーストラリア
Michael J. Fox Foundation
米国
引用
ジャーナル: Sci Adv / 年: 2024 タイトル: Interaction of PINK1 with nucleotides and kinetin. 著者: Zhong Yan Gan / Sylvie Callegari / Thanh N Nguyen / Nicholas S Kirk / Andrew Leis / Michael Lazarou / Grant Dewson / David Komander / 要旨: The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin ...The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin triphosphate (KTP) were reported to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson's disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the dodecamer assembly of () PINK1 and determine PINK1 structures bound to AMP-PNP and ADP, revealing conformational changes in the kinase N-lobe that help establish PINK1's ubiquitin binding site. Notably, we find that KTP is unable to bind PINK1 or human () PINK1 due to a steric clash with the kinase "gatekeeper" methionine residue, and mutation to Ala or Gly is required for PINK1 to bind and use KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. PINK1 M318G can be used to conditionally uncouple PINK1 stabilization and activity on mitochondria.