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Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations
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. hPINK...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679756/ https://www.ncbi.nlm.nih.gov/pubmed/28980524 http://dx.doi.org/10.7554/eLife.29985 |
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author | Kumar, Atul Tamjar, Jevgenia Waddell, Andrew D Woodroof, Helen I Raimi, Olawale G Shaw, Andrew M Peggie, Mark Muqit, Miratul MK van Aalten, Daan MF |
author_facet | Kumar, Atul Tamjar, Jevgenia Waddell, Andrew D Woodroof, Helen I Raimi, Olawale G Shaw, Andrew M Peggie, Mark Muqit, Miratul MK van Aalten, Daan MF |
author_sort | Kumar, Atul |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5679756 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-56797562017-11-13 Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations Kumar, Atul Tamjar, Jevgenia Waddell, Andrew D Woodroof, Helen I Raimi, Olawale G Shaw, Andrew M Peggie, Mark Muqit, Miratul MK van Aalten, Daan MF eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2017-10-05 /pmc/articles/PMC5679756/ /pubmed/28980524 http://dx.doi.org/10.7554/eLife.29985 Text en © 2017, Kumar et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Kumar, Atul Tamjar, Jevgenia Waddell, Andrew D Woodroof, Helen I Raimi, Olawale G Shaw, Andrew M Peggie, Mark Muqit, Miratul MK van Aalten, Daan MF Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations |
title | Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations |
title_full | Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations |
title_fullStr | Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations |
title_full_unstemmed | Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations |
title_short | Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations |
title_sort | structure of pink1 and mechanisms of parkinson's disease-associated mutations |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679756/ https://www.ncbi.nlm.nih.gov/pubmed/28980524 http://dx.doi.org/10.7554/eLife.29985 |
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