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; Daan M. F. van Aalten

doi:10.7554/eLife.29985

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)

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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 language	English
Article number	e29985
Pages (from-to)	1-16
Number of pages	16
Journal	eLife
Volume	6
Early online date	5 Oct 2017
DOIs	https://doi.org/10.7554/eLife.29985
Publication status	Published - 9 Nov 2017

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10.7554/eLife.29985Licence: CC BY

Final Published Version
© 2017, Kumar et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Final published version, 10.7 MBLicence: CC BY

Molecular Mechanisms of O-GICNAC Signalling (Investigator award)
van Aalten, D. (Investigator)
1/03/16 → 28/02/22
Project: Research
Structural Analysis of the Parkinson's Associated Kinase PINK1
Muqit, M. (Investigator) & van Aalten, D. (Investigator)
Parkinson's UK
1/11/15 → 31/10/16
Project: Research

The regulation of the Parkinson’s associated kinase PINK1
Shaw, A. (Author), Muqit, M. (Supervisor), 2020
Student thesis: Doctoral Thesis › Doctor of Philosophy

Muqit, Miratul
- MRC PPU - Professor (Clinical) of Experimental Neurology (Clinical)
Person: Academic
van Aalten, Daan
- Molecular Cell and Developmental Biology - Professor of Biological Chemistry
Person: Academic

Cite this

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title = "Structure of PINK1 and mechanisms of Parkinson's disease associated mutations",

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.",

author = "Atul Kumar and Jevgenia Tamjar and Waddell, {Andrew D.} and Woodroof, {Helen I.} and Raimi, {Olawale G.} and Shaw, {Andrew M.} and Mark Peggie and Muqit, {Miratul M. K.} and {van Aalten}, {Daan M. F.}",

note = "This work was funded by a Wellcome Trust Senior Fellowship to M.M.K.M. (101022/Z/13/Z), the Medical Research Council and a joint M.M.K.M. and D.M.F.v.A. grant from Parkinson{\textquoteright}s UK (G-1506; Fife and Ayrshire Parkinson{\textquoteright}s UK Branches). D.M.F.v.A. is funded by a Wellcome Trust Investigator Award (110061)",

year = "2017",

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doi = "10.7554/eLife.29985",

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AU - Kumar, Atul

AU - Tamjar, Jevgenia

AU - Waddell, Andrew D.

AU - Woodroof, Helen I.

AU - Raimi, Olawale G.

AU - Shaw, Andrew M.

AU - Peggie, Mark

AU - Muqit, Miratul M. K.

AU - van Aalten, Daan M. F.

N1 - This work was funded by a Wellcome Trust Senior Fellowship to M.M.K.M. (101022/Z/13/Z), the Medical Research Council and a joint M.M.K.M. and D.M.F.v.A. grant from Parkinson’s UK (G-1506; Fife and Ayrshire Parkinson’s UK Branches). D.M.F.v.A. is funded by a Wellcome Trust Investigator Award (110061)

PY - 2017/11/9

Y1 - 2017/11/9

N2 - 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.

AB - 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.

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DO - 10.7554/eLife.29985

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

Abstract

UN SDGs

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Projects

Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

Structural Analysis of the Parkinson's Associated Kinase PINK1

Student theses

The regulation of the Parkinson’s associated kinase PINK1

Profiles

Muqit, Miratul

van Aalten, Daan

Cite this