The structure of iPLA2 β reveals dimeric active sites and suggests mechanisms of regulation and localization

Nature Communications
Konstantin R MalleySergey Korolev

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.

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Citations

Sep 25, 2019·Proceedings of the National Academy of Sciences of the United States of America·Akio MoriNobutaka Hattori
Jan 9, 2019·Frontiers in Neurology·Yu-Pei GuoJi-Feng Guo
Nov 8, 2020·Molecular Genetics and Genomics : MGG·Anna LetkoSandra Scholes
Oct 23, 2020·Biomolecules·Makoto MurakamiYoshitaka Taketomi
Feb 6, 2021·Nature Chemical Biology·Wan-Yang SunValerian E Kagan
Dec 19, 2020·International Journal of Molecular Sciences·Alice BarinottiElisa Menegatti
May 1, 2021·Biomolecules·Tayleur D WhiteSasanka Ramanadham
Jun 19, 2021·Expert Opinion on Drug Discovery·Charikleia S BatsikaGeorge Kokotos
Oct 9, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Francesca MagrinelliKailash P Bhatia
Dec 19, 2021·Protein Science : a Publication of the Protein Society·Benjamin T CaswellDavid C Cantu

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Methods Mentioned

BETA
transacylation
footprinting
gel filtration
transfection
electrophoresis
X-ray
dynamic light scattering

Software Mentioned

Biotek Gen5
Phenix suite
STARANISO
Origin
SEDFIT
HKL2000
Phenix
Sculptor
Xtriage

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