7t4l

Publication Abstract from PubMed

Mutations in the protein kinase PINK1 lead to defects in mitophagy and cause autosomal recessive early onset Parkinson's Disease (EOPD)(1,2). PINK1 has many unique features that enable it to phosphorylate ubiquitin and the ubiquitin-like domain of Parkin(3-9). Structural analysis of PINK1 from diverse insect species(10-12) with and without ubiquitin provided snapshots of distinct structural states yet did not explain how PINK1 is activated. We here elucidate the activation mechanism of PINK1 by crystallography and cryo-EM. A crystal structure of unphosphorylated Pediculus humanus corporis (Ph) PINK1 resolves a previously omitted N-terminal helix revealing how unphosphorylated yet active PINK1 is oriented on mitochondria. We further reveal a 2.35 A cryo-EM structure of a symmetric PhPINK1 dimer trapped during the process of trans-autophosphorylation, and a 3.1 A cryo-EM structure of phosphorylated PhPINK1 in the process of undergoing a conformational change to become an active ubiquitin kinase. Structures and phosphorylation studies further identify a role for regulatory PINK1 oxidation. Together, our work 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.

Activation mechanism of PINK1.,Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, Geoghegan ND, Rogers KL, Leis A, Dewson G, Glukhova A, Komander D Nature. 2021 Dec 21. pii: 10.1038/s41586-021-04340-2. doi:, 10.1038/s41586-021-04340-2. PMID:34933320^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.