Structural basis of phosphatidylcholine recognition by the C2–domain of cytosolic phospholipase A2α
Year: 2019
Type: article
Abstract: Ca 2+ -stimulated translocation of cytosolic phospholipase A 2 α (cPLA 2 α) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLA 2 α preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report the structure of the cPLA 2 α 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 2 α activity. The DHPC-binding mode of the cPLA 2 α 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.
Source: eLife
DOI: 10.7554/elife.44760
Institutions: Memorial Sloan Kettering Cancer Center, Nara Institute of Science and Technology, University of Minnesota, University of South Florida, Virginia Commonwealth University Medical Center, United States Department of Veterans Affairs, Moffitt Cancer Center, James A. Haley Veterans' Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: U.S. Department of Veterans Affairs, Ministry of Education, Culture, Sports, Science and Technology, National Institutes of Health, Japan Society for the Promotion of Science, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Structural study of the transcription mechanism by GRAS/IDD family essential for root development, The utilization of photonics technology to rapidly detect bioactive lipids associated with preeclampsia development, Pixel Array Detector for X-ray Crystallography, The role of the C1P/cPLA2alpha interaction in anaphylaxis, The functional role of the cPLA2alpha/C1P interaction in sepsis resolution, G8173979607, Cancer Center Support Grant, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G954775758
OpenAlex ID: W2942676231