Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A

N. Isakov
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Abstract

The Src homology 2 (SH2) and SH3 domain-containing chicken tumor virus number 10 (CT10) regulator of kinase (Crk) adaptor proteins include three cellular members that serve as integral constituents of multiple receptor-linked signal transduction pathways. CrkI and CrkII are products of alternative RNA-splicing which is transcribed from a single gene, while Crk-like (CrkL), which is highly homologous to CrkII, is encoded by a different gene. Thanks to their modular structure, the Crk adaptor proteins can simultaneously interact with activated receptors and a wide range of effector molecules, and orchestrate the assembly of complexes containing enzymes and substrates at the receptor site. They are involved in the regulation of a large number of cellular processes which control cell growth, differentiation, transformation, and apoptosis. Cell activation-dependent tyrosine phosphorylation of CrkII and CrkL serves as a major posttranslational modification mechanism that introduces conformational changes in the proteins by promoting an intramolecular interaction between the phosphotyrosine and the self SH2 domain. The resulting conformational change induces downregulation of CrkII- and CrkL-dependent biological processes. A second type of posttranslational modification mechanism regulates the structure and function of the CrkII adaptor protein by immunophilin-mediated protein isomerization. Two of the most abundant immunophilins in T lymphocytes which function as peptidyl-prolyl cis-trans isomerases (PPIases), namely cyclophilin A (CypA) and FK506-binding proteins (FKBPs), can associate with CrkII and catalyze its reciprocal cis-trans isomerization. This mechanism is of special importance for the regulation of T lymphocyte functions and for T cell-mediated immune responses, since immunophilin inhibitors, such as cyclosporin A (CsA) and FK506, function as immunosuppressive drugs that can prevent allotransplanted graft rejection. The present manuscript focuses on selected functions of Crk adaptor proteins, predominantly in T lymphocytes, and reviews in more detail the current knowledge on the immunophilin-dependent regulation of the structure and function of the CrkII adaptor protein.
亲环蛋白A对鸡肿瘤病毒10号(CT10)激酶II (CrkII)接头蛋白的构象和功能调控
含有鸡肿瘤病毒10号(CT10)激酶调节因子(Crk)衔接蛋白的Src同源性2(SH2)和SH3结构域包括三个细胞成员,它们是多种受体连接的信号转导途径的组成部分。CrkI和CrkII是从单个基因转录的选择性RNA剪接的产物,而与CrkII高度同源的Crk样(CrkL)由不同的基因编码。由于其模块化结构,Crk衔接蛋白可以同时与激活的受体和广泛的效应分子相互作用,并在受体位点协调包含酶和底物的复合物的组装。它们参与调控大量细胞过程,控制细胞生长、分化、转化和凋亡。CrkII和CrkL的细胞活化依赖性酪氨酸磷酸化是一种主要的翻译后修饰机制,通过促进磷酸酪氨酸和自身SH2结构域之间的分子内相互作用,在蛋白质中引入构象变化。由此产生的构象变化诱导CrkII和CrkL依赖性生物过程的下调。第二种类型的翻译后修饰机制通过亲免疫蛋白介导的蛋白质异构化来调节CrkII衔接蛋白的结构和功能。T淋巴细胞中两种最丰富的亲免疫蛋白,即亲环蛋白A(CypA)和FK506结合蛋白(FKBPs),作为肽基脯氨酰顺反异构酶(PPIase),可以与CrkII结合并催化其相互顺反异构化。这一机制对T淋巴细胞功能的调节和T细胞介导的免疫反应具有特别重要的意义,因为亲免疫蛋白抑制剂,如环孢菌素A(CsA)和FK506,可作为免疫抑制药物,防止同种异体移植移植物排斥反应。本手稿主要关注Crk衔接蛋白的选定功能,主要在T淋巴细胞中,并更详细地综述了目前对CrkII衔接蛋白结构和功能的免疫亲蛋白依赖性调节的认识。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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