7T4M

Structure of dodecameric unphosphorylated Pediculus humanus (Ph) PINK1 D357A mutant

7T4M の概要

• エントリーDOI: 10.2210/pdb7t4m/pdb
• EMDBエントリー: 25680
• 分子名称: Serine/threonine-protein kinase PINK1, putative (1 entity in total)
• 機能のキーワード: pink1, kinase, transferase, mitophagy, parkinson's disease, ubiquitin, phosphorylation, phospho-ubiquitin
• 由来する生物種: Pediculus humanus corporis (human body louse)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 635155.36

構造登録者

Gan, Z.Y.,Leis, A.,Dewson, G.,Glukhova, A.,Komander, D. (登録日: 2021-12-10, 公開日: 2022-01-12, 最終更新日: 2024-02-28)

主引用文献

Gan, Z.Y.,Callegari, S.,Cobbold, S.A.,Cotton, T.R.,Mlodzianoski, M.J.,Schubert, A.F.,Geoghegan, N.D.,Rogers, K.L.,Leis, A.,Dewson, G.,Glukhova, A.,Komander, D.
Activation mechanism of PINK1.
Nature, 602:328-335, 2022

PubMed 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 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.

PubMed: 34933320
DOI: 10.1038/s41586-021-04340-2

実験手法

ELECTRON MICROSCOPY (2.48 Å)