Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation.
Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation.
复制标题
在缺乏序列保守性的情况下，本质上无序区域的保守分子识别。
DOI：
10.1101/2023.08.06.552128
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Holehouse,AlexS
中科院分区：
文献类型：
--
作者：
Alston,JhullianJ;Soranno,Andrea;Holehouse,AlexS
固有无序区(IDR)对细胞功能至关重要，但当通过多个序列比对来评估时，通常似乎缺乏序列保守性。这就提出了一个问题，即尽管序列发生了巨大的变化，但功能是否以及如何在这些区域被编码和保存。为了解决这个问题，我们应用粗粒度分子动力学模拟来研究冠状病毒核衣壳蛋白的非特异性RNA结合。冠状病毒核衣壳蛋白由多个散布的、无序的和折叠的结构域组成，它们与RNA结合。在这里，我们集中在冠状病毒核衣壳蛋白的前两个结构域，无序的N末端结构域(NTD)，紧随其后的是折叠的RNA结合域(RBD)。虽然NTD在进化过程中高度可变，但RBD在结构上是保守的。这种结合使NTD-RBD成为一个方便的模型系统，可以探索折叠结构域附近的IDR之间的相互作用，以及IDR序列的变化如何影响伴侣的分子识别。我们的结果揭示了由NTD中氨基酸的组成和精确顺序编码的令人惊讶的序列特异性。根据序列的不同，NTD的存在可以抑制或增强RNA结合。尽管这种敏感性，在保留某些序列特征的同时，NTD序列的大规模变化是可能的。因此，尽管NTD序列和RBD表面化学发生了大规模变化，但在核衣壳蛋白同源物中发现了一个构象保守的动态和无序的RNA：蛋白质复合体。综上所述，这些洞察力揭示了无序区域保持功能特征的能力，尽管它们的序列具有可变性。
Intrinsically disordered regions (IDRs) are critical for cellular function, yet often appear to lack sequence conservation when assessed by multiple sequence alignments. This raises the question of if and how function can be encoded and preserved in these regions despite massive sequence variation. To address this question, we have applied coarse-grained molecular dynamics simulations to investigate non-specific RNA binding of coronavirus nucleocapsid proteins. Coronavirus nucleocapsid proteins consist of multiple interspersed disordered and folded domains that bind RNA. We focussed here on the first two domains of coronavirus nucleocapsid proteins, the disordered N-terminal domain (NTD) followed by the folded RNA binding domain (RBD). While the NTD is highly variable across evolution, the RBD is structurally conserved. This combination makes the NTD-RBD a convenient model system to explore the interplay between an IDR adjacent to a folded domain and how changes in IDR sequence can influence molecular recognition of a partner. Our results reveal a surprising degree of sequence-specificity encoded by both the composition and the precise order of the amino acids in the NTD. The presence of an NTD can—depending on the sequence—either suppress or enhance RNA binding. Despite this sensitivity, large-scale variation in NTD sequences is possible while certain sequence features are retained. Consequently, a conformationally conserved dynamic and disordered RNA: protein complex is found across nucleocapsid protein orthologs, despite large-scale changes in both NTD sequence and RBD surface chemistry. Taken together, these insights shed light on the ability of disordered regions to preserve functional characteristics despite their sequence variability.