Protein or peptide: Serine/threonine-protein kinase PINK1, putative
Function / homology
Function and homology information
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 / protein serine/threonine kinase activity / ATP binding / metal ion binding / cytosol Similarity search - Function
: / 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 Similarity search - Domain/homology
National Health and Medical Research Council (NHMRC, Australia)
United States
Michael J. Fox Foundation
United States
Citation
Journal: Nature / Year: 2022 Title: Activation mechanism of PINK1. Authors: Zhong Yan Gan / Sylvie Callegari / Simon A Cobbold / Thomas R Cotton / Michael J Mlodzianoski / Alexander F Schubert / Niall D Geoghegan / Kelly L Rogers / Andrew Leis / Grant Dewson / Alisa ...Authors: Zhong Yan Gan / Sylvie Callegari / Simon A Cobbold / Thomas R Cotton / Michael J Mlodzianoski / Alexander F Schubert / Niall D Geoghegan / Kelly L Rogers / Andrew Leis / Grant Dewson / Alisa Glukhova / David Komander / Abstract: Mutations in the protein kinase PINK1 lead to defects in mitophagy and cause autosomal recessive early onset Parkinson's disease. PINK1 has many unique features that enable it to phosphorylate ...Mutations in the protein kinase PINK1 lead to defects in mitophagy and cause autosomal recessive early onset Parkinson's disease. PINK1 has many unique features that enable it to phosphorylate ubiquitin and the ubiquitin-like domain of Parkin. Structural analysis of PINK1 from diverse insect species with and without ubiquitin provided snapshots of distinct structural states yet did not explain how PINK1 is activated. Here we elucidate the activation mechanism of PINK1 using crystallography and cryo-electron microscopy (cryo-EM). A crystal structure of unphosphorylated Pediculus humanus corporis (Ph; human body louse) PINK1 resolves an N-terminal helix, revealing the orientation of unphosphorylated yet active PINK1 on the mitochondria. We further provide a cryo-EM structure of a symmetric PhPINK1 dimer trapped during the process of trans-autophosphorylation, as well as a cryo-EM structure of phosphorylated PhPINK1 undergoing a conformational change to an active ubiquitin kinase state. Structures and phosphorylation studies further identify a role for regulatory PINK1 oxidation. Together, our research delineates the complete activation mechanism of PINK1, illuminates how PINK1 interacts with the mitochondrial outer membrane and reveals how PINK1 activity may be modulated by mitochondrial reactive oxygen species.
History
Deposition
Dec 10, 2021
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Header (metadata) release
Jan 12, 2022
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Map release
Jan 12, 2022
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Update
Jan 12, 2022
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Current status
Jan 12, 2022
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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