Structure of PINK1 and mechanisms of Parkinson's disease associated mutations

Atul Kumar, Jevgenia Tamjar, Andrew D. Waddell, Helen I. Woodroof, Olawale G. Raimi, Andrew M. Shaw, Mark Peggie, Miratul M. K. Muqit (Lead / Corresponding author), Daan M. F. van Aalten (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

Mutations in the human kinase PINK1 (hPINK1) are associated with autosomal recessive early-onset Parkinson's disease (PD). hPINK1 activates Parkin E3 ligase activity, involving phosphorylation of ubiquitin and the Parkin ubiquitin-like (Ubl) domain via as yet poorly understood mechanisms. hPINK1 is unusual amongst kinases due to the presence of three loop insertions of unknown function. We report the structure of Tribolium castaneum PINK1 (TcPINK1), revealing several unique extensions to the canonical protein kinase fold. The third insertion, together with autophosphorylation at residue Ser205, contributes to formation of a bowl-shaped binding site for ubiquitin. We also define a novel structural element within the second insertion that is held together by a distal loop that is critical for TcPINK1 activity. The structure of TcPINK1 explains how PD-linked mutations that lie within the kinase domain result in hPINK1 loss-of-function and provides a platform for the exploration of small molecule modulators of hPINK1.

Original languageEnglish
Article numbere29985
Pages (from-to)1-16
Number of pages16
JournaleLife
Volume6
Early online date5 Oct 2017
DOIs
Publication statusPublished - 9 Nov 2017

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    Student Theses

    The regulation of the Parkinson’s associated kinase PINK1

    Author: Shaw, A., 2020

    Supervisor: Muqit, M. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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    Muqit, Miratul

    • MRC PPU - Professor (Clinical) & Personal Chair of Experimental Neurology (Clinical)

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    van Aalten, Daan

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