Cofilin and ADF are cytoskeleton remodeling proteins that cooperatively bind and fragment actin filaments. Bound cofilin molecules do not directly interact with each other, indicating that cooperative binding of cofilin is mediated by the actin filament lattice. Cofilactin is therefore a model system for studying allosteric regulation of self-assembly. How cofilin binding changes structural and mechanical properties of actin filaments is well established. Less is known about the interaction energies and the thermodynamics of filament fragmentation, which describes the collective manner in which the cofilin concentration controls mean actin filament length. Here, we provide a general thermodynamic framework for allosteric regulation of self-assembly, and we use the theory to predict the interaction energies of experimental actin filament length distributions over a broad range of cofilin binding densities and for multiple cofilactin variants. We find that bound cofilin induces changes in nearby actin-actin interactions, and that these allosteric effects are propagated along the filament to affect up to four neighboring cofilin-binding sites (i.e., beyond nearest-neighbor allostery). The model also predicts that cofilin differentially stabilizes and destabilizes longitudinal versus lateral actin-actin interactions, and that the magnitude, range, asymmetry, and even the sign of these interaction energies can be altered using different actin and cofilin mutational variants. These results demonstrate that the theoretical framework presented here can provide quantitative thermodynamic information governing cooperative protein binding and filament length regulation, thus revealing nanometer length-scale interactions from micron length-scale “wet-lab” measurements.

中文翻译：

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蛋白质细丝长度的定向变构调节

Cofilin和ADF是细胞骨架重塑蛋白，可协同结合并片段化肌动蛋白丝。结合的cofilin分子彼此之间不直接相互作用，表明cofilin的协同结合是由肌动蛋白丝晶格介导的。因此，Cofilactin是研究自组装变构调节的模型系统。肌动蛋白丝结合如何改变肌动蛋白丝的结构和机械性能是众所周知的。关于相互作用能和细丝断裂的热力学的了解较少，这描述了cofilin浓度控制平均肌动蛋白丝长度的集体方式。在这里，我们为自组装的变构调节提供了一个通用的热力学框架，并且我们使用该理论预测了广泛的cofilin结合密度和多种cofilactin变体在实验肌动蛋白丝长度分布的相互作用能。我们发现结合的纤溶蛋白诱导附近的肌动蛋白-肌动蛋白相互作用的变化，并且这些变构效应沿细丝传播，从而影响多达四个相邻的纤丝蛋白结合位点（即，超出最近的邻居构形）。该模型还预测，cofilin差异性地稳定和破坏了纵向肌动蛋白与肌动蛋白-肌动蛋白之间的相互作用，并且可以通过使用不同的肌动蛋白和cofilin突变体来改变这些相互作用能的大小，范围，不对称甚至符号。