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Structural Insights into Phospholipase Cɛ: A Multi‐Method Biophysical Approach
Author(s) -
GarlandKuntz Elisabeth E.,
Vago Frank S.,
Sieng Monita,
Chakravarthy Srinivas,
Jiang Wen,
Lyon Angeline M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.816.9
Subject(s) - phospholipase c , phosphatidylinositol , second messenger system , microbiology and biotechnology , phospholipase , enzyme , kinase , gq alpha subunit , inositol , signal transduction , biology , g protein coupled receptor , biochemistry , chemistry , receptor
Phospholipase C (PLC) enzymes hydrolyze phosphatidylinositol lipids to produce second messengers, including inositol‐1,4,5‐triphosphate and diacylgycerol, which increase intracellular calcium and activate protein kinase C, respectively. PLCɛ contributes to cardiac hypertrophy, where it is chronically activated by the small G protein Rap1A, as well as to oncogenic Ras signaling pathways downstream of receptor tyrosine kinases. Specifically, Rap1A and Ras proteins are proposed to bind to the C‐terminal Ras‐association (RA) domain of PLCɛ, promoting conformational changes that increase lipase activity and/or membrane association. However, the role of the RA domains in PLCɛ activity is poorly understood. We are using small‐angle X‐ray scattering, electron microscopy, and biochemical approaches to determine the roles of the RA domains in basal regulation and activity upon G protein activation. These results provide the first structural insights into this essential enzyme and improve understanding of its roles in cardiovascular disease and cancer. Support or Funding Information This work is supported by the Showalter Foundation, Purdue Center for Cancer Research, and the American Heart Association (Grant 16SDG29920017 to AML).