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The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization

Calcium-independent phospholipase A(2)β (iPLA(2)β) regulates important physiological processes including inflammation, calcium homeostasis and apoptosis. It is genetically linked to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underl...

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Autores principales: Malley, Konstantin R., Koroleva, Olga, Miller, Ian, Sanishvili, Ruslan, Jenkins, Christopher M., Gross, Richard W., Korolev, Sergey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823874/
https://www.ncbi.nlm.nih.gov/pubmed/29472584
http://dx.doi.org/10.1038/s41467-018-03193-0
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author Malley, Konstantin R.
Koroleva, Olga
Miller, Ian
Sanishvili, Ruslan
Jenkins, Christopher M.
Gross, Richard W.
Korolev, Sergey
author_facet Malley, Konstantin R.
Koroleva, Olga
Miller, Ian
Sanishvili, Ruslan
Jenkins, Christopher M.
Gross, Richard W.
Korolev, Sergey
author_sort Malley, Konstantin R.
collection PubMed
description Calcium-independent phospholipase A(2)β (iPLA(2)β) regulates important physiological processes including inflammation, calcium homeostasis and apoptosis. It is genetically linked to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underlying iPLA(2)β-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA(2)β that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. They are surrounded by ankyrin repeat domains that adopt an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. The structure and additional solution studies suggest that both catalytic domains can be bound and allosterically inhibited by a single calmodulin. These features suggest mechanisms of iPLA(2)β cellular localization and activity regulation, providing a basis for inhibitor development. Furthermore, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA(2)β in the brain.
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spelling pubmed-58238742018-02-26 The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization Malley, Konstantin R. Koroleva, Olga Miller, Ian Sanishvili, Ruslan Jenkins, Christopher M. Gross, Richard W. Korolev, Sergey Nat Commun Article Calcium-independent phospholipase A(2)β (iPLA(2)β) regulates important physiological processes including inflammation, calcium homeostasis and apoptosis. It is genetically linked to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underlying iPLA(2)β-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA(2)β that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. They are surrounded by ankyrin repeat domains that adopt an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. The structure and additional solution studies suggest that both catalytic domains can be bound and allosterically inhibited by a single calmodulin. These features suggest mechanisms of iPLA(2)β cellular localization and activity regulation, providing a basis for inhibitor development. Furthermore, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA(2)β in the brain. Nature Publishing Group UK 2018-02-22 /pmc/articles/PMC5823874/ /pubmed/29472584 http://dx.doi.org/10.1038/s41467-018-03193-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Malley, Konstantin R.
Koroleva, Olga
Miller, Ian
Sanishvili, Ruslan
Jenkins, Christopher M.
Gross, Richard W.
Korolev, Sergey
The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
title The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
title_full The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
title_fullStr The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
title_full_unstemmed The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
title_short The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
title_sort structure of ipla(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823874/
https://www.ncbi.nlm.nih.gov/pubmed/29472584
http://dx.doi.org/10.1038/s41467-018-03193-0
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