Department of Chemistry, Institute of Biomedical Sciences and Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 200438, China.
Biomolecules. 2019 Feb 26;9(3):81. doi: 10.3390/biom9030081.
Protein interactions involving intrinsically disordered proteins (IDPs) greatly extend the range of binding mechanisms available to proteins. In interactions employing coupled folding and binding, IDPs undergo disorder-to-order transitions to form a complex with a well-defined structure. In many other cases, IDPs retain structural plasticity in the final complexes, which have been defined as the fuzzy complexes. While a large number of fuzzy complexes have been characterized with variety of fuzzy patterns, many of the interactions are between an IDP and a structured protein. Thus, whether two IDPs can interact directly to form a fuzzy complex without disorder-to-order transition remains an open question. Recently, two studies of interactions between IDPs (4.1G-CTD/NuMA and H1/ProTα) have found a definite answer to this question. Detailed characterizations combined with nuclear magnetic resonance (NMR), single-molecule Förster resonance energy transfer (smFRET) and molecular dynamics (MD) simulation demonstrate that direct interactions between these two pairs of IDPs do form fuzzy complexes while retaining the conformational dynamics of the isolated proteins, which we name as the extremely fuzzy complexes. Extreme fuzziness completes the full spectrum of protein-protein interaction modes, suggesting that a more generalized model beyond existing binding mechanisms is required. Previous models of protein interaction could be applicable to some aspects of the extremely fuzzy interactions, but in more general sense, the distinction between native and nonnative contacts, which was used to understand protein folding and binding, becomes obscure. Exploring the phenomenon of extreme fuzziness may shed new light on molecular recognition and drug design.
涉及无规卷曲蛋白质（IDPs）的蛋白质相互作用极大地扩展了蛋白质可用的结合机制的范围。在采用耦合折叠和结合的相互作用中，IDP 经历无序到有序的转变，形成具有明确定义结构的复合物。在许多其他情况下，IDP 在最终复合物中保持结构的可塑性，这些复合物被定义为模糊复合物。虽然已经用各种模糊模式对大量模糊复合物进行了表征，但许多相互作用是在 IDP 和结构蛋白之间发生的。因此，两个 IDP 是否可以直接相互作用形成模糊复合物而不经历无序到有序的转变仍然是一个悬而未决的问题。最近，两项关于 IDP 之间相互作用的研究（4.1G-CTD/NuMA 和 H1/ProTα）对这个问题给出了明确的答案。详细的特征分析结合核磁共振（NMR）、单分子Förster 共振能量转移（smFRET）和分子动力学（MD）模拟表明，这两对 IDP 之间的直接相互作用确实形成了模糊复合物，同时保留了分离蛋白质的构象动力学，我们将其命名为极其模糊复合物。极端模糊性完成了蛋白质-蛋白质相互作用模式的完整范围，表明需要超越现有结合机制的更广义模型。蛋白质相互作用的先前模型可能适用于极其模糊相互作用的某些方面，但更一般地说，用于理解蛋白质折叠和结合的天然和非天然接触之间的区别变得模糊。探索极端模糊性的现象可能会为分子识别和药物设计提供新的思路。
