内在无序蛋白质
计算生物学
蛋白质结构
蛋白质结构域
CTD公司
领域(数学分析)
互补性(分子生物学)
折叠(DSP实现)
生物
蛋白质-蛋白质相互作用
计算机科学
生物系统
生物物理学
遗传学
数学
生物化学
电气工程
地质学
工程类
数学分析
海洋学
基因
作者
Xiuhong Hu,Yang Xu,Chenchen Wang,Yufeng Liu,Lu Zhang,Jiahai Zhang,Wenning Wang,Quan Chen,Haiyan Liu
标识
DOI:10.1073/pnas.2305603120
摘要
An increasing number of protein interaction domains and their targets are being found to be intrinsically disordered proteins (IDPs). The corresponding target recognition mechanisms are mostly elusive because of challenges in performing detailed structural analysis of highly dynamic IDP-IDP complexes. Here, we show that by combining recently developed computational approaches with experiments, the structure of the complex between the intrinsically disordered C-terminal domain (CTD) of protein 4.1G and its target IDP region in NuMA can be dissected at high resolution. First, we carry out systematic mutational scanning using dihydrofolate reductase-based protein complementarity analysis to identify essential interaction regions and key residues. The results are found to be highly consistent with an α/β-type complex structure predicted by AlphaFold2 (AF2). We then design mutants based on the predicted structure using a deep learning protein sequence design method. The solved crystal structure of one mutant presents the same core structure as predicted by AF2. Further computational prediction and experimental assessment indicate that the well-defined core structure is conserved across complexes of 4.1G CTD with other potential targets. Thus, we reveal that an intrinsically disordered protein interaction domain uses an α/β-type structure module formed through synergistic folding to recognize broad IDP targets. Moreover, we show that computational prediction and experiment can be jointly applied to segregate true IDP regions from the core structural domains of IDP-IDP complexes and to uncover the structure-dependent mechanisms of some otherwise elusive IDP-IDP interactions.
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