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Activation of Phospholipase C β by Gβγ and Gα_q Involves C-Terminal Rearrangement to Release Autoinhibition.

ABSTRACT: Phospholipase C (PLC) enzymes hydrolyze phosphoinositide lipids to inositol phosphates and diacylglycerol. Direct activation of PLCβ by Gα_q and/or Gβγ subunits mediates signaling by Gq and some Gi coupled G-protein-coupled receptors (GPCRs), respectively. PLCβ isoforms contain a unique C-terminal extension, consisting of proximal and distal C-terminal domains (CTDs) separated by a flexible linker. The structure of PLCβ3 bound to Gα_q is known, however, for both Gα_q and Gβγ; the mechanism for PLCβ activation on membranes is unknown. We examined PLCβ2 dynamics on membranes using hydrogen-deuterium exchange mass spectrometry (HDX-MS). Gβγ caused a robust increase in dynamics of the distal C-terminal domain (CTD). Gα_q showed decreased deuterium incorporation at the Gα_q binding site on PLCβ. In vitro Gβγ-dependent activation of PLC is inhibited by the distal CTD. The results suggest that disruption of autoinhibitory interactions with the CTD leads to increased PLCβ hydrolase activity.

SUBMITTER: Fisher IJ

PROVIDER: S-EPMC7891876 | biostudies-literature |

REPOSITORIES: biostudies-literature

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