The crystal and cryo-EM structures of PLCγ2 reveal dynamic inter-domain recognitions in autoinhibition
Shin, Y.-C.; Plummer-Medeiros, A. M.; Mungenast, A.; Choi, H.-w.; TenDyke, K.; Zhu, X.; Shepard, J.; Zhuang, N.; Hu, L.; Qian, D.; Song, K.; Xu, C.; Wang, J.; Poda, S. B.; Liao, M.; Chen, Y.
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Abstract/SummaryPhospholipase C gamma 2 (PLC{gamma}2) plays important roles in cell signaling downstream of various membrane receptors. PLC{gamma}2 contains a multi-domain 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 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 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 new structural insights into PLC{gamma}2 regulation that will facilitate future mechanistic studies to understand the entire activation process.
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