Direct observation of conformational dynamics of the PH domain in phospholipases Cε and {beta} may contribute to subfamily-specific roles in regulation [Protein Structure and Folding] (Journal of Biological Chemistry)

Phospholipase C (PLC) enzymes produce second messengers that increase the intracellular Ca2+ concentration and activate protein kinase C (PKC). These enzymes also share a highly conserved arrangement of core domains. However, the contributions of the individual domains to regulation are poorly understood, particularly in isoforms lacking high-resolution information, such as PLC?. Here, we used small-angle X-ray scattering (SAXS), EM, and functional assays to gain insights into the molecular architecture of PLC?, revealing that its PH domain is conformationally dynamic and essential for activity. We further demonstrate that the PH domain of PLC? exhibits similar dynamics in solution that are substantially different from its conformation observed in multiple previously reported crystal structures. We propose that this conformational heterogeneity contributes to subfamily-specific differences in activity and regulation by extracellular signals.