Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A,2α
Document Type
Article
Publication Date
2019
Digital Object Identifier (DOI)
https://doi.org/10.7554/eLife.44760
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 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.
Rights Information
This work is licensed under a Creative Commons Attribution 4.0 License.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
eLife, v. 8, art. e44760
Scholar Commons Citation
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 A,2α" (2019). Molecular Biosciences Faculty Publications. 73.
https://digitalcommons.usf.edu/bcm_facpub/73
