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

Phospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multidomain 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 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 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 structural insights into PLCγ2 regulation that will facilitate future mechanistic studies to understand the entire activation process.

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Publication Details

Journal
Science Advances
Published
2024-11-29
DOI
https://doi.org/10.1126/sciadv.adn6037
Citations
4
Primary Topic
Fibroblast Growth Factor Research
Type
article
Field-Weighted Citation Impact
0.94

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

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

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article en
4 citations

Abstract

Phospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multidomain 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 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 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 structural insights into PLCγ2 regulation that will facilitate future mechanistic studies to understand the entire activation process.

Science AdvancesVol. 10(48)
Harvard University (US), University of Massachusetts Chan Medical School (US), Eisai (United States) (US), Viva Biotech (China) (CN)
Eisai
Openalex Percentile: Top 24%
Fibroblast Growth Factor Research
0.94
DOIOpen Access PDFOpenAlex
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