Structure of human PINK1 at a mitochondrial TOM-VDAC array
Details
Publication Year 2025-04-18,Volume 388,Issue #6744,Page 303-310
Journal Title
Science
Abstract
Mutations in the ubiquitin kinase PINK1 cause early-onset Parkinson's disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-angstrom resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial translocase of the outer membrane (TOM) and voltage-dependent anion channel (VDAC) complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.
Publisher
AAAS
Keywords
Humans; Carrier Proteins/chemistry; Cryoelectron Microscopy; *Membrane Transport Proteins/chemistry; *Mitochondria/metabolism; *Mitochondrial Membrane Transport Proteins/chemistry; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; *Protein Kinases/chemistry/ultrastructure/metabolism/genetics; Protein Multimerization; Receptors, Cell Surface/chemistry; *Voltage-Dependent Anion Channel 2/chemistry
Research Division(s)
Ubiquitin Signalling; Advanced Technology And Biology; Structural Biology; Structural Biology; Advanced Technology and Biology
PubMed ID
40080546
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2025-03-19 09:29:39
Last Modified: 2025-05-06 09:18:28
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