The importance of the compact disordered state in the fuzzy interactions between intrinsically disordered proteins

文献类型： 外文期刊

第一作者： Wang, Dan

作者： Wang, Dan;Song, Xingyu;Yang, Maohua;Weng, Jingwei;Wang, Wenning;Wang, Dan;Song, Xingyu;Yang, Maohua;Weng, Jingwei;Wang, Wenning;Wu, Shaowen;Wang, Dongdong;Zhang, Wolun;Huang, Shaohui;Huang, Shaohui;Liu, Zhijun

作者机构：

期刊名称：CHEMICAL SCIENCE （ 影响因子：9.969； 五年影响因子：9.974 ）

ISSN： 2041-6520

年卷期： 2022 年 13 卷 8 期

页码：

收录情况： SCI

摘要： The intrinsically disordered C-terminal domain (CTD) of protein 4.1G is able to specifically bind a 26-residue intrinsically disordered region of NuMA, forming a dynamic fuzzy complex. As one of a few cases of extremely fuzzy interactions between two intrinsically disordered proteins/regions (IDPs/IDRs) without induced folding, the principle of the binding is unknown. Here, we combined experimental and computational methods to explore the detailed mechanism of the interaction between 4.1G-CTD and NuMA. MD simulations suggest that the kinetic hub states in the structure ensemble of 4.1G-CTD are favorable in the fuzzy complex. The feature of these hub states is that the binding 'hot spot' motifs beta A and beta B exhibit beta strand propensities and are well packed to each other. The binding between 4.1G-CTD and NuMA is disrupted at low pH, which changes the intramolecular packing of 4.1G-CTD and weakens the packing between beta A and beta B motifs. Low pH conditions also lead to increased hydrodynamic radius and acceleration of backbone dynamics of 4.1G-CTD. All these results underscore the importance of tertiary structural arrangements and overall compactness of 4.1G-CTD in its binding to NuMA, i.e. the compact disordered state of 4.1G-CTD is crucial for binding. Different from the short linear motifs (SLiMs) that are often found to mediate IDP interactions, 4.1G-CTD functions as an intrinsically disordered domain (IDD), which is a functional and structural unit similar to conventional protein domains. This work sheds light on the molecular recognition mechanism of IDPs/IDRs and expands the conventional structure-function paradigm in protein biochemistry.

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