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首页> 外文期刊>Journal of Molecular Biology >Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target.
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Kinetic recognition of the retinoblastoma tumor suppressor by a specific protein target.

机译：通过特定的蛋白质靶标对视网膜母细胞瘤肿瘤抑制剂的动力学识别。

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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 T-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.
机译：视网膜母细胞瘤抑癌剂（Rb）在细胞周期控制中起关键作用，并与各种类型的人类癌症相关。 Rb结合LxCxE基序，LtCxE基序存在于许多细胞和病毒蛋白中，例如AdE1A，SV40大T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。对RbAB结合HPV E7癌蛋白的详细动力学研究表明，含LxCxE的E7片段通过快速的二态反应结合，强烈受静电相互作用的作用。相反，全长E7通过多步骤过程进行结合，该过程包括E7构象体之间的预平衡，由LxCxE基序引导的快速静电驱动缔合步骤和缓慢的构象重排。这种动力学复杂性是由于E7的构象可塑性和内在无序性，以及两种蛋白质中都存在多个相互作用表面而引起的。高风险和低风险类型的E7N域之间的亲和力差异由其解离速率解释。实际上，由于Rb在大型蛋白质相互作用网络的中心，因此快速和紧密的识别为病毒蛋白质的破坏提供了优势，因为生理和病理相互作用的平衡由动力学配体竞争决定。 LxCxE母题在固有无序域内的定位提供了快速的，扩散控制的相互作用，使病毒蛋白可以胜过生理目标。我们描述了Rb与蛋白质配体，同时包含LxCxE的模型目标和范式本质上无序的病毒癌蛋白的相互作用机制。

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