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Title: Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A 2α

Abstract

Ca 2+-stimulated translocation of cytosolic phospholipase A 2α (cPLA 2α) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLA 2α preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report the structure of the cPLA 2α C2-domain (at 2.2 Å resolution), which contains bound 1,2-dihexanoyl- sn-glycero-3-phosphocholine (DHPC) and Ca 2+ ions. Two Ca 2+ are complexed at previously reported locations in the lipid-free C2-domain. One of these Ca 2+ ions, along with a third Ca 2+, 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 cPLA 2α activity. The DHPC-binding mode of the cPLA 2α 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.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3];  [4]; ORCiD logo [2]; ORCiD logo [5]; ORCiD logo [6];  [5]; ORCiD logo [2]
  1. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, United States; Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Takayama, Japan
  2. Hormel Institute, University of Minnesota, Austin, United States
  3. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University Medical Center, Richmond, United States; Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, United States
  4. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University Medical Center, Richmond, United States
  5. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, United States
  6. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, United States; Research Service, James A. Haley Veterans Hospital, Tampa, United States; The Moffitt Cancer Center, Tampa, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
DOE - OTHERNIHFOREIGN
OSTI Identifier:
1526068
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 8; Journal Issue: 2019; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Hirano, Yoshinori, Gao, Yong-Guang, Stephenson, Daniel J., Vu, Ngoc T., Malinina, Lucy, Simanshu, Dhirendra K., Chalfant, Charles E., Patel, Dinshaw J., and Brown, Rhoderick E. Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α. United States: N. p., 2019. Web. doi:10.7554/eLife.44760.
Hirano, Yoshinori, Gao, Yong-Guang, Stephenson, Daniel J., Vu, Ngoc T., Malinina, Lucy, Simanshu, Dhirendra K., Chalfant, Charles E., Patel, Dinshaw J., & Brown, Rhoderick E. Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α. United States. doi:10.7554/eLife.44760.
Hirano, Yoshinori, Gao, Yong-Guang, Stephenson, Daniel J., Vu, Ngoc T., Malinina, Lucy, Simanshu, Dhirendra K., Chalfant, Charles E., Patel, Dinshaw J., and Brown, Rhoderick E. Fri . "Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α". United States. doi:10.7554/eLife.44760.
@article{osti_1526068,
title = {Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α},
author = {Hirano, Yoshinori and Gao, Yong-Guang and Stephenson, Daniel J. and Vu, Ngoc T. and Malinina, Lucy and Simanshu, Dhirendra K. and Chalfant, Charles E. and Patel, Dinshaw J. and Brown, Rhoderick E.},
abstractNote = {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.},
doi = {10.7554/eLife.44760},
journal = {eLife},
issn = {2050-084X},
number = 2019,
volume = 8,
place = {United States},
year = {2019},
month = {5}
}

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