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Nat Commun. 2018 Feb 22;9(1):765. doi: 10.1038/s41467-018-03193-0.

The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization.

Author information

1
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
2
GM/CA@APS, Advanced Photon Source, Argonne National Laboratory, Argonne, IL, 60439, USA.
3
Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO, 63110, USA.
4
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
5
Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
6
Department of Chemistry, Washington University, Saint Louis, MO, 63130, USA.
7
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA. sergey.korolev@health.slu.edu.

Abstract

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. Furthermore, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA2β in the brain.

PMID:
29472584
PMCID:
PMC5823874
DOI:
10.1038/s41467-018-03193-0
[Indexed for MEDLINE]
Free PMC Article

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