The Structural and Dynamic Response of MAGI-1 PDZ1 with Noncanonical Domain Boundaries to the Binding of Human Papillomavirus E6
The Structural and Dynamic Response of MAGI-1 PDZ1 with Noncanonical Domain Boundaries to the Binding of Human Papillomavirus E6
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DOI：
10.1016/j.jmb.2011.01.015
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发表时间：
2011-03-11
影响因子：
5.6
通讯作者：
Atkinson, R. Andrew
中科院分区：
文献类型：
--
作者：
Charbonnier, Sebastian;Nomine, Yves;Atkinson, R. Andrew
PDZ结构域是在细胞质蛋白中发现的参与信号通路和亚细胞运输的蛋白质相互作用结构域。它们在控制细胞生长、细胞极性和细胞粘附方面的作用使这一蛋白家族成为癌症发展过程中的靶点。“高风险”人乳头瘤病毒（hpv）的癌蛋白E6靶向这些网络枢纽，有助于有效地破坏细胞过程。利用核磁共振技术，我们解决了MAGI-1的第二PDZ结构域扩展结构（MAGI-1 PDZ1）单独与HPV16 E6的c端衍生肽结合的三维溶液结构，并表征了主链动力学和氢键结合时发生的变化。结合事件导致PDZ结构域c端尾部高频运动的猝灭，该结构域与典型的X-[T/S]-X-[L/V]结合基序上游的肽接触。在PDZ结构域的c端侧翼区域设计的突变导致E6肽的结合亲和力显著降低。这一详细的分析支持了PDZ结构域对结合事件的全局响应的概念，其影响传播到远端位点，并揭示了规范PDZ结构域边界两侧序列的意外作用。(C) 2011 Elsevier Ltd.版权所有。
PDZ domains are protein interaction domains that are found in cytoplasmic proteins involved in signaling pathways and subcellular transport. Their roles in the control of cell growth, cell polarity, and cell adhesion in response to cell contact render this family of proteins targets during the development of cancer. Targeting of these network hubs by the oncoprotein E6 of "high-risk" human papillomaviruses (HPVs) serves to effect the efficient disruption of cellular processes. Using NMR, we have solved the three-dimensional solution structure of an extended construct of the second PDZ domain of MAGI-1 (MAGI-1 PDZ1) alone and bound to a peptide derived from the C-terminus of HPV16 E6, and we have characterized the changes in backbone dynamics and hydrogen bonding that occur upon binding. The binding event induces quenching of high-frequency motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical X-[T/S]-X-[L/V] binding motif. Mutations designed in the C-terminal flanking region of the PDZ domain resulted in a significant decrease in binding affinity for E6 peptides. This detailed analysis supports the notion of a global response of the PDZ domain to the binding event, with effects propagated to distal sites, and reveals unexpected roles for the sequences flanking the canonical PDZ domain boundaries. (C) 2011 Elsevier Ltd. All rights reserved.