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

Autor:	Kumar A; Division of Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom.; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom., Tamjar J; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom., Waddell AD; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom., Woodroof HI; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom., Raimi OG; Division of Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom., Shaw AM; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom., Peggie M; Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, Dundee, United Kingdom., Muqit MM; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom.; School of Medicine, University of Dundee, Dundee, United Kingdom., van Aalten DM; Division of Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2017 Oct 05; Vol. 6. Date of Electronic Publication: 2017 Oct 05.
DOI:	10.7554/eLife.29985
Abstrakt:	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 ( Tc PINK1), 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 Tc PINK1 activity. The structure of Tc PINK1 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.
Databáze:	MEDLINE
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