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

Phospholipase C gamma 2 (PLC gamma 2) plays important roles in cell signaling downstream of various membrane receptors. PLC gamma 2 contains a multidomain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLC gamma 2 activity modulation. Here we determined three structures of human PLC gamma 2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the Src homology 3 (SH3) domain in the inhibitory region, and its previously unknown interaction with a carboxyl-terminal helical domain in the core region. We also determined a structure of PLC gamma 2 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 PLC gamma 2. Our results provide structural insights into PLC gamma 2 regulation that will facilitate future mechanistic studies to understand the entire activation process.