Dynamics of allosteric regulation of the phospholipase C-γ isozymes upon recruitment to membranes

被引:5
作者
Siraliev-Perez, Edhriz [1 ]
Stariha, Jordan T. B. [2 ]
Hoffmann, Reece M. [2 ]
Temple, Brenda R. S. [1 ]
Zhang, Qisheng [1 ,3 ,4 ]
Hajicek, Nicole [5 ]
Jenkins, Meredith L. [2 ]
Burke, John E. [2 ,6 ]
Sondek, John [1 ,4 ,5 ]
机构
[1] Univ North Carolina Chapel Hill, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
[2] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC, Canada
[3] Univ North Carolina Chapel Hill, Div Chem Biol & Med Chem, Sch Pharm, Chapel Hill, NC USA
[4] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Sch Pharm, Chapel Hill, NC 27599 USA
[5] Univ North Carolina Chapel Hill, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA
[6] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC, Canada
来源
ELIFE | 2022年 / 11卷
基金
美国国家科学基金会; 美国国家卫生研究院; 加拿大自然科学与工程研究理事会;
关键词
phospholipase C; PLCG1; hydrogen-deuterium exchange; HDX-MS; protein dynamics; allosteric regulation; None; PHOSPHORYLATION-INDUCED ACTIVATION; TYROSINE RESIDUES; MEDIATED ACTIVATION; BINDING-SITE; SH2; DOMAINS; C-GAMMA-1; PLC; SUBSTRATE; RAC; STIMULATION;
D O I
10.7554/eLife.77809
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Numerous receptor tyrosine kinases and immune receptors activate phospholipase C-gamma (PLC-gamma) isozymes at membranes to control diverse cellular processes including phagocytosis, migration, proliferation, and differentiation. The molecular details of this process are not well understood. Using hydrogen-deuterium exchange mass spectrometry, we show that PLC-gamma 1 is relatively inert to lipid vesicles that contain its substrate, phosphatidylinositol 4,5-bisphosphate (PIP2), unless first bound to the kinase domain of the fibroblast growth factor receptor (FGFR1). Exchange occurs throughout PLC-gamma 1 and is exaggerated in PLC-gamma 1 containing an oncogenic substitution (D1165H) that allosterically activates the lipase. These data support a model whereby initial complex formation shifts the conformational equilibrium of PLC-gamma 1 to favor activation. This receptor-induced priming of PLC-gamma 1 also explains the capacity of a kinase-inactive fragment of FGFR1 to modestly enhance the lipase activity of PLC-gamma 1 operating on lipid vesicles but not a soluble analog of PIP2 and highlights potential cooperativity between receptor engagement and membrane proximity. Priming is expected to be greatly enhanced for receptors embedded in membranes and nearly universal for the myriad of receptors and co-receptors that bind the PLC-gamma isozymes.
引用
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页数:22
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