The crystal and cryo-EM structures of PLCγ2 reveal dynamic inter-domain recognitions in autoinhibition

Abstract

Abstract/SummaryPhospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multi-domain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLCγ2 activity modulation. Here we determined three structures of human PLCγ2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the SH3 domain in the inhibitory region, and its previously unknown interaction with a C-terminal helical domain in the core region. We also determined a structure of PLCγ2 bound to the kinase domain of fibroblast growth factor receptor 1 (FGFR1), which demonstrates the recognition of FGFR1 by the nSH2 domain in the inhibitory region of PLCγ2. Our results provide new structural insights into PLCγ2 regulation that will facilitate future mechanistic studies to understand the entire activation process.