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.

doi:10.1101/2023.09.07.556539

bioRxiv · 10.1101/2023.09.07.556539

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

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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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.. 2023-09-08. The crystal and cryo-EM structures of PLCγ2 reveal dynamic inter-domain recognitions in autoinhibition. https://doi.org/10.1101/2023.09.07.556539

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