Kinetic Recognition of the Retinoblastoma Tumor Suppressor by a Specific Protein Target
Kinetic Recognition of the Retinoblastoma Tumor Suppressor by a Specific Protein Target
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DOI：
10.1016/j.jmb.2011.07.015
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发表时间：
2011-09-16
影响因子：
5.6
通讯作者：
de Prat-Gay, Gonzalo
中科院分区：
文献类型：
--
作者：
Chemes, Lucia B.;Sanchez, Ignacio E.;de Prat-Gay, Gonzalo
视网膜母细胞瘤肿瘤抑制因子（Rb）在细胞周期控制中起着关键作用，并与各种类型的人类癌症有关。Rb与LxCxE基序结合，该基序存在于许多细胞和病毒蛋白中，如AdE1A、SV40大1抗原和人乳头瘤病毒（HPV）E7，所有这些都有助于揭示肿瘤抑制、细胞周期控制和基因表达的基本机制。RbAB与HPV E7癌蛋白结合的详细动力学研究表明，含有LxCxE的E7片段通过静电相互作用强烈支持的快速双态反应结合。相反，全长E7通过多步骤过程结合，包括E7构象异构体之间的预平衡，由LxCxE基序引导的快速静电驱动的缔合步骤和缓慢的构象重排。这种动力学复杂性源于E7的构象可塑性和内在无序性，以及两种蛋白质中存在的多个相互作用表面。来自高风险和低风险类型的E7N结构域之间的亲和力差异由其解离速率解释。事实上，由于Rb是在一个大的蛋白质相互作用网络的中心，快速和紧密的识别提供了一个优势，通过病毒蛋白质的破坏，其中生理和病理相互作用的平衡是由动力学配体竞争。LxCxE基序在固有无序结构域内的定位提供了快速的、扩散控制的相互作用，使得病毒蛋白质能够胜过生理靶标。我们描述了Rb与蛋白质配体的相互作用机制，同时含有LxCxE的模型靶点，以及一种典型的内在无序的病毒癌蛋白。(C)2011爱思唯尔有限公司保留所有权利。
The retinoblastoma tumor suppressor (Rb) plays a key role in cell cycle control and is linked to various types of human cancer. Rb binds to the LxCxE motif, present in a number of cellular and viral proteins such as AdE1A, SV40 large 1-antigen and human papillomavirus (HPV) E7, all instrumental in revealing fundamental mechanisms of tumor suppression, cell cycle control and gene expression. A detailed kinetic study of RbAB binding to the HPV E7 oncoprotein shows that an LxCxE-containing E7 fragment binds through a fast two-state reaction strongly favored by electrostatic interactions. Conversely, full-length E7 binds through a multistep process involving a pre-equilibrium between E7 conformers, a fast electrostatically driven association step guided by the LxCxE motif and a slow conformational rearrangement. This kinetic complexity arises from the conformational plasticity and intrinsically disordered nature of E7 and from multiple interaction surfaces present in both proteins. Affinity differences between E7N domains from high- and low-risk types are explained by their dissociation rates. In fact, since Rb is at the center of a large protein interaction network, fast and tight recognition provides an advantage for disruption by the viral proteins, where the balance of physiological and pathological interactions is dictated by kinetic ligand competition. The localization of the LxCxE motif within an intrinsically disordered domain provides the fast, diffusion-controlled interaction that allows viral proteins to outcompete physiological targets. We describe the interaction mechanism of Rb with a protein ligand, at the same time an LxCxE-containing model target, and a paradigmatic intrinsically disordered viral oncoprotein. (C) 2011 Elsevier Ltd. All rights reserved.