Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α

Ca2+-stimulated translocation of cytosolic phospholipase A2α (cPLA2α) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLA2α preference for phosphatidylcholine (PC)-enriched membranes have remained elusiv...

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Autores principales:	Yoshinori Hirano, Yong-Guang Gao, Daniel J Stephenson, Ngoc T Vu, Lucy Malinina, Dhirendra K Simanshu, Charles E Chalfant, Dinshaw J Patel, Rhoderick E Brown
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2019
Materias:	C2-domain of cytoplasmic phospholipase A2 alpha structural mapping of phosphatidylcholine binding site structure-function analyses Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/af6a1b2fae9e4f1fa435261f48886fe1
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spelling	oai:doaj.org-article:af6a1b2fae9e4f1fa435261f48886fe12021-11-29T17:09:39ZStructural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α10.7554/eLife.447602050-084Xe44760https://doaj.org/article/af6a1b2fae9e4f1fa435261f48886fe12019-05-01T00:00:00Zhttps://elifesciences.org/articles/44760https://doaj.org/toc/2050-084XCa2+-stimulated translocation of cytosolic phospholipase A2α (cPLA2α) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLA2α preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report the structure of the cPLA2α C2-domain (at 2.2 Å resolution), which contains bound 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) and Ca2+ ions. Two Ca2+ are complexed at previously reported locations in the lipid-free C2-domain. One of these Ca2+ions, along with a third Ca2+, bridges the C2-domain to the DHPC phosphate group, which also interacts with Asn65. Tyr96 plays a key role in lipid headgroup recognition via cation–π interaction with the PC trimethylammonium group. Mutagenesis analyses confirm that Tyr96 and Asn65 function in PC binding selectivity by the C2-domain and in the regulation of cPLA2α activity. The DHPC-binding mode of the cPLA2α C2-domain, which differs from phosphatidylserine or phosphatidylinositol 4,5-bisphosphate binding by other C2-domains, expands and deepens knowledge of the lipid-binding mechanisms mediated by C2-domains.Yoshinori HiranoYong-Guang GaoDaniel J StephensonNgoc T VuLucy MalininaDhirendra K SimanshuCharles E ChalfantDinshaw J PatelRhoderick E BrowneLife Sciences Publications LtdarticleC2-domain of cytoplasmic phospholipase A2 alphastructural mapping of phosphatidylcholine binding sitestructure-function analysesMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 8 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	C2-domain of cytoplasmic phospholipase A2 alpha structural mapping of phosphatidylcholine binding site structure-function analyses Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	C2-domain of cytoplasmic phospholipase A2 alpha structural mapping of phosphatidylcholine binding site structure-function analyses Medicine R Science Q Biology (General) QH301-705.5 Yoshinori Hirano Yong-Guang Gao Daniel J Stephenson Ngoc T Vu Lucy Malinina Dhirendra K Simanshu Charles E Chalfant Dinshaw J Patel Rhoderick E Brown Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
description	Ca2+-stimulated translocation of cytosolic phospholipase A2α (cPLA2α) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLA2α preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report the structure of the cPLA2α C2-domain (at 2.2 Å resolution), which contains bound 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) and Ca2+ ions. Two Ca2+ are complexed at previously reported locations in the lipid-free C2-domain. One of these Ca2+ions, along with a third Ca2+, bridges the C2-domain to the DHPC phosphate group, which also interacts with Asn65. Tyr96 plays a key role in lipid headgroup recognition via cation–π interaction with the PC trimethylammonium group. Mutagenesis analyses confirm that Tyr96 and Asn65 function in PC binding selectivity by the C2-domain and in the regulation of cPLA2α activity. The DHPC-binding mode of the cPLA2α C2-domain, which differs from phosphatidylserine or phosphatidylinositol 4,5-bisphosphate binding by other C2-domains, expands and deepens knowledge of the lipid-binding mechanisms mediated by C2-domains.
format	article
author	Yoshinori Hirano Yong-Guang Gao Daniel J Stephenson Ngoc T Vu Lucy Malinina Dhirendra K Simanshu Charles E Chalfant Dinshaw J Patel Rhoderick E Brown
author_facet	Yoshinori Hirano Yong-Guang Gao Daniel J Stephenson Ngoc T Vu Lucy Malinina Dhirendra K Simanshu Charles E Chalfant Dinshaw J Patel Rhoderick E Brown
author_sort	Yoshinori Hirano
title	Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
title_short	Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
title_full	Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
title_fullStr	Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
title_full_unstemmed	Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
title_sort	structural basis of phosphatidylcholine recognition by the c2–domain of cytosolic phospholipase a2α
publisher	eLife Sciences Publications Ltd
publishDate	2019
url	https://doaj.org/article/af6a1b2fae9e4f1fa435261f48886fe1
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_version_	1718407243911659520

Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α

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