Structure of PINK1 in complex with its substrate ubiquitin

Alexander F. Schubert, Christina Gladkova, Els Pardon, Jane L. Wagstaff, Stefan M. V. Freund, Jan Steyaert, Sarah L. Maslen and David Komander ()
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Alexander F. Schubert: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue
Christina Gladkova: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue
Els Pardon: VIB-VUB Center for Structural Biology, VIB
Jane L. Wagstaff: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue
Stefan M. V. Freund: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue
Jan Steyaert: VIB-VUB Center for Structural Biology, VIB
Sarah L. Maslen: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue
David Komander: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue

Nature, 2017, vol. 552, issue 7683, 51-56

Abstract: Abstract Autosomal-recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular the genes encoding the E3 ubiquitin ligase Parkin (PARK2, also known as PRKN) and its upstream protein kinase PINK1 (also known as PARK6). PINK1 phosphorylates both ubiquitin and the ubiquitin-like domain of Parkin on structurally protected Ser65 residues, triggering mitophagy. Here we report a crystal structure of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph)PINK1 bound to 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 N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible Ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of Ser65 in a phosphate-accepting position. The structure also explains how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and reveals the molecular basis of AR-JP-causing mutations, some of which disrupt ubiquitin binding.

Date: 2017
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DOI: 10.1038/nature24645

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