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Molecular Mechanism of Rap1A‐Dependent Activation of PLCɛ
Author(s) -
Sieng Monita,
GarlandKuntz Elisabeth E.,
Lyon Angeline M.
Publication year - 2018
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.2018.32.1_supplement.686.9
Subject(s) - phosphatidylinositol , phospholipase c , diacylglycerol kinase , gq alpha subunit , inositol , microbiology and biotechnology , phosphoinositide phospholipase c , gtpase , biology , g protein coupled receptor , signal transduction , chemistry , receptor , protein kinase c , biochemistry
Phospholipase C (PLC) enzymes hydrolyze phosphatidylinositol lipids to produce diacylglycerol (DAG) and inositol phosphates, to activate protein kinase C (PKC) and downstream signaling pathways, including cell growth and survival. The PLCɛ subfamily has emerged as a key player in cardiovascular health, where it is required for maximum contractility. However, prolonged activation of PLCɛ results in cardiac hypertrophy and heart failure through its ability to regulate hypertrophic gene expression. This process is regulated by the small GTPase Rap1A, which is activated downstream of β‐adrenergic receptors. Rap1A binds to the C‐terminal Ras association (RA) domain of PLCɛ, simultaneously translocating the complex to the perinuclear region and activating PLCɛ. However, the molecular mechanism of this process is not known. We seek to characterize the interactions between Rap1A and PLCɛ using structural and functional studies to map the Rap1A binding site on PLCɛ and determine whether activation results in conformational changes that release autoinhibition and/or increase membrane association. These studies provide the first molecular details of the Rap1A‐dependent activation of PLCɛ and opens the door to the development of new therapeutic strategies for treating cardiac hypertrophy. Support or Funding Information American Heart Association Scientist Development Grant (16SDG29920017) to A.M.L.; Purdue Center for Cancer Research This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .