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Title: The structure of iPLA 2β reveals dimeric active sites and suggests mechanisms of regulation and localization

Abstract

Calcium-independent phospholipase A 2β (iPLA 2β) 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 2β-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA 2β 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 2β cellular localization and activity regulation, providing a basis for inhibitor development. Lastly, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA 2β in the brain.

Authors:
 [1];  [1];  [1];  [2];  [3];  [4]; ORCiD logo [1]
  1. Saint Louis Univ. School of Medicine, St. Louis, MO (United States)
  2. Argonne National Lab. (ANL), Argonne, IL (United States)
  3. Washington Univ. School of Medicine, Saint Louis, MO (United States)
  4. Washington Univ. School of Medicine, Saint Louis, MO (United States); Washington Univ., Saint Louis, MO (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1465195
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Malley, Konstantin R., Koroleva, Olga, Miller, Ian, Sanishvili, Ruslan, Jenkins, Christopher M., Gross, Richard W., and Korolev, Sergey. The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization. United States: N. p., 2018. Web. doi:10.1038/s41467-018-03193-0.
Malley, Konstantin R., Koroleva, Olga, Miller, Ian, Sanishvili, Ruslan, Jenkins, Christopher M., Gross, Richard W., & Korolev, Sergey. The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization. United States. doi:10.1038/s41467-018-03193-0.
Malley, Konstantin R., Koroleva, Olga, Miller, Ian, Sanishvili, Ruslan, Jenkins, Christopher M., Gross, Richard W., and Korolev, Sergey. Thu . "The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization". United States. doi:10.1038/s41467-018-03193-0. https://www.osti.gov/servlets/purl/1465195.
@article{osti_1465195,
title = {The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization},
author = {Malley, Konstantin R. and Koroleva, Olga and Miller, Ian and Sanishvili, Ruslan and Jenkins, Christopher M. and Gross, Richard W. and Korolev, Sergey},
abstractNote = {Calcium-independent phospholipase A2β (iPLA2β) 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 iPLA2β-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA2β 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 iPLA2β cellular localization and activity regulation, providing a basis for inhibitor development. Lastly, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA2β in the brain.},
doi = {10.1038/s41467-018-03193-0},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {2}
}

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Works referenced in this record:

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925