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Title: Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition

Abstract

Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. The GIVD cPLA2 (cPLA2δ) is a potential drug target for developing a selective therapeutic agent for the treatment of psoriasis. Here, we present two X-ray structures of human cPLA2δ, capturing an apo state, and in complex with a substrate-like inhibitor. Comparison of the apo and inhibitor-bound structures reveals conformational changes in a flexible cap that allows the substrate to access the relatively buried active site, providing new insight into the mechanism for substrate recognition. The cPLA2δ structure reveals an unexpected second C2 domain that was previously unrecognized from sequence alignments, placing cPLA2δ into the class of membrane-associated proteins that contain a tandem pair of C2 domains. Furthermore, our structures elucidate novel inter-domain interactions and define three potential calcium-binding sites that are likely important for regulation and activation of enzymatic activity. These findings provide novel insights into the molecular mechanisms governing cPLA2's function in signal transduction.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE; NCINIGMS
OSTI Identifier:
1346231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Biology; Journal Volume: 428; Journal Issue: 13
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Wang, Hui, Klein, Michael G., Snell, Gyorgy, Lane, Weston, Zou, Hua, Levin, Irena, Li, Ke, and Sang, Bi-Ching. Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition. United States: N. p., 2016. Web. doi:10.1016/j.jmb.2016.05.012.
Wang, Hui, Klein, Michael G., Snell, Gyorgy, Lane, Weston, Zou, Hua, Levin, Irena, Li, Ke, & Sang, Bi-Ching. Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition. United States. doi:10.1016/j.jmb.2016.05.012.
Wang, Hui, Klein, Michael G., Snell, Gyorgy, Lane, Weston, Zou, Hua, Levin, Irena, Li, Ke, and Sang, Bi-Ching. 2016. "Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition". United States. doi:10.1016/j.jmb.2016.05.012.
@article{osti_1346231,
title = {Structure of Human GIVD Cytosolic Phospholipase A2 Reveals Insights into Substrate Recognition},
author = {Wang, Hui and Klein, Michael G. and Snell, Gyorgy and Lane, Weston and Zou, Hua and Levin, Irena and Li, Ke and Sang, Bi-Ching},
abstractNote = {Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. The GIVD cPLA2 (cPLA2δ) is a potential drug target for developing a selective therapeutic agent for the treatment of psoriasis. Here, we present two X-ray structures of human cPLA2δ, capturing an apo state, and in complex with a substrate-like inhibitor. Comparison of the apo and inhibitor-bound structures reveals conformational changes in a flexible cap that allows the substrate to access the relatively buried active site, providing new insight into the mechanism for substrate recognition. The cPLA2δ structure reveals an unexpected second C2 domain that was previously unrecognized from sequence alignments, placing cPLA2δ into the class of membrane-associated proteins that contain a tandem pair of C2 domains. Furthermore, our structures elucidate novel inter-domain interactions and define three potential calcium-binding sites that are likely important for regulation and activation of enzymatic activity. These findings provide novel insights into the molecular mechanisms governing cPLA2's function in signal transduction.},
doi = {10.1016/j.jmb.2016.05.012},
journal = {Journal of Molecular Biology},
number = 13,
volume = 428,
place = {United States},
year = 2016,
month = 7
}