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eLife Volume 8 ,2019-12-30
Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations
Biochemistry and Chemical Biology
Nicole Hajicek 1 Nicholas C Keith 1 Edhriz Siraliev-Perez 2 Brenda RS Temple 2 , 3 Weigang Huang 4 Qisheng Zhang 1 , 4 , 5 T Kendall Harden 1 John Sondek 1 , 2 , 5
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DOI:10.7554/eLife.51700
Received 2019-09-06, accepted for publication 2019-12-30, Published 2019-12-30
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摘要

Direct activation of the human phospholipase C-γ isozymes (PLC-γ1, -γ2) by tyrosine phosphorylation is fundamental to the control of diverse biological processes, including chemotaxis, platelet aggregation, and adaptive immunity. In turn, aberrant activation of PLC-γ1 and PLC-γ2 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-γ isozymes are available, these structures are insufficient to define how release of basal autoinhibition is coupled to phosphorylation-dependent enzyme activation. Here, we describe the first high-resolution structure of a full-length PLC-γ isozyme and use it to underpin a detailed model of their membrane-dependent regulation. Notably, an interlinked set of regulatory domains integrates basal autoinhibition, tyrosine kinase engagement, and additional scaffolding functions with the phosphorylation-dependent, allosteric control of phospholipase activation. The model also explains why mutant forms of the PLC-γ isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.

关键词

None;cancer;molecular dynamics;X-ray crystallography;interfacial regulation;allostery;phospholipase C

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© 2019, Hajicek et al
http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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Nicole Hajicek,Nicholas C Keith,Edhriz Siraliev-Perez,Brenda RS Temple,Weigang Huang,Qisheng Zhang,T Kendall Harden,John Sondek. Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations. eLife ,Vol.8(2019)

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