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Structural basis of phosphatidylcholine recognition by the C2-domain of cytosolic phospholipase A(2)alpha

  1. Author:
    Hirano, Yoshinori
    Gao, Yong-Guang
    Stephenson, Daniel J.
    Vu, Ngoc T.
    Malinina, Lucy
    Simanshu,Dhirendra
    Chalfant, Charles E.
    Patel, Dinshaw J.
    Brown, Rhoderick E.

  2. Author Address

    Mem Sloan Kettering Canc Ctr, Struct Biol Program, 1275 York Ave, New York, NY 10021 USA.Nara Inst Sci & Technol NAIST, Grad Sch Biol Sci, Takayama, Japan.Univ Minnesota, Hormel Inst, Austins, MN 55912 USA.Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Med Ctr, Richmond, VA 23298 USA.Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA.James A Haley Vet Hosp, Res Serv, Tampa, FL 33612 USA.H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA.Univ Tokyo, Grad Pharmaceut Sci, Lab Prot Struct Biol, Tokyo, Japan.Frederick Natl Lab Canc Res, Frederick, MD USA.
    1. Year: 2019
    2. Date: MAY 3
  2. Journal: ELIFE
  3. ELIFE SCIENCES PUBLICATIONS LTD,
    1. 8
  5. Type of Article: Article
  6. Article Number: e44760
  7. ISSN: 2050-084X
  1. Abstract:

    Ca2+-stimulated translocation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLA(2)alpha preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report the structure of the cPLA(2)alpha C2-domain (at 2.2 A degrees 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-pi 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)alpha activity. The DHPC-binding mode of the cPLA(2)alpha 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.

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External Sources

  1. View Full Text
  2. DOI: 10.7554/eLife.44760
  3. View record in Web of Science®
  4. WOS: 000470762200001

Library Notes

  1. Fiscal Year: FY2018-2019
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