Structural basis of phosphatidylcholine recognition by the C2-domain of cytosolic phospholipase A2α
Abstract
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 cPLA2α C2-domain structure (2.2Å resolution) containing bound 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) and Ca2+ ions. Two Ca2+ are complexed at locations previously reported for lipid-free C2-domain. One of these Ca2+ along with a third Ca2+ bridge 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 Tyr96 and Asn65 function in PC binding selectivity by C2-domain and regulation of cPLA2α activity. The differing DHPC-binding mode of cPLA2α C2-domain, compared to phosphatidylserine or phosphatidylinositol 4,5-bisphosphate binding by other C2-domains, expands and deepens knowledge of lipid-binding mechanisms mediated by C2-domains.
Data availability
Diffraction data have been deposited in PDB under the accession code 6IEJ
Article and author information
Author details
Funding
National Institutes of Health (HL125353)
- Rhoderick E Brown
Ministry of Education, Culture, Sports, Science, and Technology
- Yoshinori Hirano
U.S. Department of Veterans Affairs (I BX001792)
- Charles E Chalfant
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arun Radhakrishnan, University of Texas Southwestern Medical Center, United States
Version history
- Received: December 28, 2018
- Accepted: May 3, 2019
- Accepted Manuscript published: May 3, 2019 (version 1)
- Version of Record published: June 5, 2019 (version 2)
- Version of Record updated: November 29, 2021 (version 3)
Copyright
© 2019, Hirano et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
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