Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123 Uppsala, Sweden.
Phys Chem Chem Phys. 2014 Apr 14;16(14):6323-31. doi: 10.1039/c3cp54226b. Epub 2013 Dec 6.
Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins are very common and instrumental for cellular signaling. Recently, a number of studies have investigated the kinetic binding mechanisms of IDPs and IDRs. These results allow us to draw conclusions about the energy landscape for the coupled binding and folding of disordered proteins. The association rate constants of IDPs cover a wide range (10(5)-10(9) M(-1) s(-1)) and are largely governed by long-range charge-charge interactions, similarly to interactions between well-folded proteins. Off-rate constants also differ significantly among IDPs (with half-lives of up to several minutes) but are usually around 0.1-1000 s(-1), allowing for rapid dissociation of complexes. Likewise, affinities span from pM to μM suggesting that the low-affinity high-specificity concept for IDPs is not straightforward. Overall, it appears that binding precedes global folding although secondary structure elements such as helices may form before the protein-protein interaction. Short IDPs bind in apparent two-state reactions whereas larger IDPs often display complex multi-step binding reactions. While the two extreme cases of two-step binding (conformational selection and induced fit) or their combination into a square mechanism is an attractive model in theory, it is too simplistic in practice. Experiment and simulation suggest a more complex energy landscape in which IDPs bind targets through a combination of conformational selection before binding (e.g., secondary structure formation) and induced fit after binding (global folding and formation of short-range intermolecular interactions).
无规蛋白（IDPs）和蛋白质的无规区域（IDRs）非常常见，是细胞信号传导的关键。最近，许多研究调查了 IDPs 和 IDRs 的动力学结合机制。这些结果使我们能够得出关于无序蛋白质结合和折叠的耦合能景观的结论。IDPs 的缔合速率常数范围很广（10^5-10^9 M^-1 s^-1），主要受长程电荷-电荷相互作用的控制，类似于折叠良好的蛋白质之间的相互作用。离解速率常数在 IDPs 之间也有很大差异（半衰期长达数分钟），但通常在 0.1-1000 s^-1 左右，允许复合物快速解离。同样，亲和力范围从 pM 到 μM，表明 IDPs 的低亲和力高特异性概念并不简单。总体而言，尽管在蛋白质-蛋白质相互作用之前可能会形成二级结构元件（如螺旋），但似乎是结合先于全局折叠。短的 IDPs 以明显的两态反应结合，而较大的 IDPs 通常显示复杂的多步结合反应。虽然两步结合的两个极端情况（构象选择和诱导契合）或它们组合成一个正方形机制在理论上是一个有吸引力的模型，但在实践中过于简单化。实验和模拟表明，在该无序蛋白质通过结合前的构象选择（例如二级结构形成）和结合后的诱导契合（全局折叠和形成短程分子间相互作用）相结合的情况下，存在更复杂的能量景观。
