Structural basis of phosphatidylcholine recognition by the C2-domain of cytosolic phospholipase Aα.
Publication Type:Journal Article
Source:Elife, Volume 8 (2019)
<p>Ca-stimulated translocation of cytosolic phospholipase Aα (cPLAα) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLAα preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report cPLAα C2-domain structure (2.2Å resolution) containing bound 1,2-dihexanoyl--glycero-3-phosphocholine (DHPC) and Ca ions. Two Ca are complexed at locations previously reported for lipid-free C2-domain. One of these Ca along with a third Ca 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 cPLAα activity. The differing DHPC-binding mode of cPLAα 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.</p>