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Scaffold Protein SLP-76 Primes PLC gamma 1 for Activation by ITK-Mediated Phosphorylation

机译:支架蛋白SLP-76灌注PLCγ1以通过ITK介导的磷酸化激活

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摘要

Activation of the phospholipase, PLC gamma 1, is critical for proper T cell signaling following antigen receptor engagement. In T cells, the Tec family kinase, interleukin-2-induced tyrosine kinase (ITK), phosphorylates PLC gamma 1 at tyrosine 783 (Y783) leading to activation of phospholipase function and subsequent production of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. In this work, we demonstrate that PLC gamma 1 can be primed for ITK-mediated phosphorylation on Y783 by a specific region of the adaptor protein, SLP-76. The SLP-76 phosphotyrosine-containing sequence, pY(173)IDR, does not conform to the canonical recognition motif for an SH2 domain yet binds with significant affinity to the C-terminal SH2 domain of PLC gamma 1 (SH2C). The SLP-76 pY(173) motif competes with the autoinhibited conformation surrounding the SH2C domain of PLC gamma 1 leading to exposure of the ITK recognition element on the PLC gamma 1 SH2 domain and release of the target tyrosine, Y783. These data contribute to the evolving model for the molecular events occurring early in the T cell activation process. (C) 2015 Elsevier Ltd. All rights reserved.
机译:磷脂酶PLC gamma 1的激活对于抗原受体参与后正确的T细胞信号传导至关重要。在T细胞中,Tec家族激酶(白介素2诱导的酪氨酸激酶(ITK))在酪氨酸783(Y783)处使PLCγ1磷酸化,从而激活磷脂酶功能并随后产生第二种信使肌醇1,4,5-三磷酸和二酰基甘油。在这项工作中,我们证明了PLCγ1可以通过衔接蛋白SLP-76的特定区域引发Y783上ITK介导的磷酸化。包含SLP-76磷酸酪氨酸的序列pY(173)IDR不符合SH2域的规范识别基序,但与PLCγ1(SH2C)的C端SH2域具有显着亲和力。 SLP-76 pY(173)基序与PLCγ1的SH2C域周围的自抑制构象竞争,从而导致ITK识别元件在PLCγ1 SH2域上暴露并释放靶酪氨酸Y783。这些数据有助于在T细胞活化过程早期发生的分子事件的进化模型。 (C)2015 Elsevier Ltd.保留所有权利。

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