biostudies-literatureWang DMinistry of Science and Technology of the People's Republic of ChinaNational Natural Science Foundation of China2363-2377https://www.ebi.ac.uk/biostudies/studies/S-EPMC8864705biostudies-literatureUnknown13(8)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 βA and βB exhibit β strand propensities and are well packed to each other. The binding between 4.Chemical scienceThe importance of the compact disordered state in the fuzzy interactions between intrinsically disordered proteins.PMC88647052016YFA05017022187701722073018Zhang WHuang SLiu ZWang DYang MWu SWeng JWang WSong XfalseThe importance of the compact disordered state in the fuzzy interactions between intrinsically disordered proteins.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 βA and βB exhibit β strand propensities and are well packed to each other. The binding between 4.2022-01-01T00:00:00Z2022 Feb2025-04-19T13:17:36.328Z2025-04-19T13:17:36.328ZS-EPMC88647053531048210.1039/d1sc06825c