Structural Insights into Phospholipase Cɛ Function

Abstract

Phospholipase Cɛ (PLCɛ) is a member of the PLC family of enzymes that hydrolyze phosphatidylinositol lipids downstream of G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). PLCɛ is unique among the PLC superfamily as it contains an N‐terminal CDC25 domain, which has guanine nucleotide exchange factor (GEF) activity towards small G proteins Rap1A, and two C‐terminal Ras association (RA) domains. The best characterized pathway leading to PLCɛ activation is mediated through β‐adrenergic receptor (βARs) signaling. Stimulation of these receptors culminates in the activation of the small GTPase, Rap1A, which binds directly to PLCɛ and translocates the complex to the Golgi. There, PLCɛ hydrolyzes phosphatidylinol‐4‐phosphate (PI4P). Prolonged activation of this pathway results in increased expression of hypertrophy‐related genes. However, how the structural basis of PLCɛ activity under basal conditions and upon activation by Rap1A are unknown. Towards this end, we have obtained the first high‐resolution insights into a catalytically active PLCɛ variant. These studies, together with biochemical analysis of the intramolecular contacts observed in the structure, provide the first molecular insights into this enzyme.Support or Funding InformationThis research is supported by American Heart Association Scientist Development Grant 16SDG29920017 and NIH 1R01HL141076‐01 to A.M.LThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.