Direct observation of conformational dynamics of the PH domain in phospholipases Cϵ and β may contribute to subfamily-specific roles in regulation.

Elisabeth E Garland-Kuntz, Frank S Vago, Monita Sieng, Michelle Van Camp, Srinivas Chakravarthy, Arryn Blaine, Clairissa Corpstein, Wen Jiang, Angeline M Lyon

The Journal of biological chemistry 2018 Nov 09

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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 PLCϵ. Here, we used small-angle X-ray scattering (SAXS), EM, and functional assays to gain insights into the molecular architecture of PLCϵ, revealing that its PH domain is conformationally dynamic and essential for activity. We further demonstrate that the PH domain of PLCβ 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.

Citation

Elisabeth E Garland-Kuntz, Frank S Vago, Monita Sieng, Michelle Van Camp, Srinivas Chakravarthy, Arryn Blaine, Clairissa Corpstein, Wen Jiang, Angeline M Lyon. Direct observation of conformational dynamics of the PH domain in phospholipases Cϵ and β may contribute to subfamily-specific roles in regulation. The Journal of biological chemistry. 2018 Nov 09;293(45):17477-17490