The Inherent Dynamics and Interaction Sites of the SARS-CoV-2 Nucleocapsid N-Terminal Region.
The Inherent Dynamics and Interaction Sites of the SARS-CoV-2 Nucleocapsid N-Terminal Region.
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DOI：
10.1016/j.jmb.2021.167108
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发表时间：
2021-07-23
影响因子：
5.6
通讯作者：
Eisenmesser EZ
中科院分区：
文献类型：
--
作者：
Redzic JS;Lee E;Born A;Issaian A;Henen MA;Nichols PJ;Blue A;Hansen KC;D'Alessandro A;Vögeli B;Eisenmesser EZ
核衣壳蛋白是由SARS-CoV-2编码的四种结构蛋白之一，在包装病毒RNA和操纵宿主细胞机制中起着核心作用，但其在核苷酸结合中的动态行为和混杂性使得标准结构方法难以解决其原子分辨率细节。为了开始解决SARS-CoV-2核衣壳蛋白与RNA和宿主细胞的相互作用沿着动态行为，我们特别关注折叠的N-末端结构域（NTD）及其侧翼区域，使用核磁共振溶液研究。在这里进行的研究揭示了一个大的相互作用，其中包括温度依赖性的自关联介导的无序侧翼区，也作为结合位点的宿主细胞亲环蛋白-A，而核苷酸结合主要是由中央NTD核心介导的。包括弛豫实验在内的核磁共振研究揭示了这种病毒蛋白质复杂的动力学性质。具体而言，虽然大部分N-末端核心结构域表现出微毫秒运动，但中心β-发夹在皮秒时间尺度上显示出提高的固有灵活性，并且残基176-209的富含丝氨酸/丝氨酸的区域经历多次交换现象。总的来说，这些研究已经开始揭示核衣壳蛋白动力学的复杂性及其与其生物靶标的优选相互作用位点。
The nucleocapsid protein is one of four structural proteins encoded by SARS-CoV-2 and plays a central role in packaging viral RNA and manipulating the host cell machinery, yet its dynamic behavior and promiscuity in nucleotide binding has made standard structural methods to address its atomic-resolution details difficult. To begin addressing the SARS-CoV-2 nucleocapsid protein interactions with both RNA and the host cell along with its dynamic behavior, we have specifically focused on the folded N-terminal domain (NTD) and its flanking regions using nuclear magnetic resonance solution studies. Studies performed here reveal a large repertoire of interactions, which includes a temperature-dependent self-association mediated by the disordered flanking regions that also serve as binding sites for host cell cyclophilin-A while nucleotide binding is largely mediated by the central NTD core. NMR studies that include relaxation experiments have revealed the complicated dynamic nature of this viral protein. Specifically, while much of the N-terminal core domain exhibits micro-millisecond motions, a central β-hairpin shows elevated inherent flexibility on the pico-nanosecond timescale and the serine/arginine-rich region of residues 176–209 undergoes multiple exchange phenomena. Collectively, these studies have begun to reveal the complexities of the nucleocapsid protein dynamics and its preferred interaction sites with its biological targets.
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