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Structure of PINK1 in complex with its substrate ubiquitin

DOI: 10.1038/nature24645 DOI Help

Authors: Alexander Schubert (Medical Research Council Laboratory of Molecular Biology) , Christina Gladkova (Medical Research Council Laboratory of Molecular Biology) , Els Pardon (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Jane L. Wagstaff (Medical Research Council Laboratory of Molecular Biology) , Stefan M. V. Freund (Medical Research Council Laboratory of Molecular Biology) , Jan Steyaert (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Sarah L. Maslen (Medical Research Council Laboratory of Molecular Biology) , David Komander (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: October 2017

Abstract: Autosomal recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular in the E3 ubiquitin ligase Parkin (PARK2), and in its upstream protein kinase PINK1 (PARK6). PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like domain on structurally protected Ser65 to trigger mitophagy. We here report a crystal structure of a nanobody-stabilised complex between Pediculus humanus corporis (Ph)PINK1 with ubiquitin in the ‘C-terminally retracted’ (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the PINK1 N-lobe binds ubiquitin via a unique insertion. The flexible Ser65-loop in the Ub-CR conformation reaches the activation segment, facilitating placement of Ser65 in a phosphate accepting position. The structure further explains how autophosphorylation in the N-lobe stabilises structurally and functionally important insertions, and reveals the molecular basis for AR-JP causing mutations, some of which disrupt ubiquitin binding.

Journal Keywords: Ubiquitylation; Phosphorylation; X-ray crystallography; Mechanisms of disease

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

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