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Cryo EM map of full length PLC gamma 2 in autoinhibition state
Structural highlights
DiseasePLCG2_HUMAN Defects in PLCG2 are the cause of familial cold autoinflammatory syndrome type 3 (FCAS3) [MIM:614468. An autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritis in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders.[1] FunctionPLCG2_HUMAN The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling. Publication Abstract from PubMedPhospholipase C gamma 2 (PLCgamma2) plays important roles in cell signaling downstream of various membrane receptors. PLCgamma2 contains a multidomain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLCgamma2 activity modulation. Here we determined three structures of human PLCgamma2 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 PLCgamma2 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 PLCgamma2. Our results provide structural insights into PLCgamma2 regulation that will facilitate future mechanistic studies to understand the entire activation process. The crystal and cryo-EM structures of PLCgamma2 reveal dynamic interdomain recognitions in autoinhibition.,Shin YC, Plummer-Medeiros AM, Mungenast A, Choi HW, TenDyke K, Zhu X, Shepard J, Sanders K, Zhuang N, Hu L, Qian D, Song K, Xu C, Wang J, Poda SB, Liao M, Chen Y Sci Adv. 2024 Nov 29;10(48):eadn6037. doi: 10.1126/sciadv.adn6037. Epub 2024 Nov , 29. PMID:39612343[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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