Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
Division of Physical Chemistry, Department of Chemistry, Lund University, Box 124, 22100 Lund, Sweden.
Curr Opin Struct Biol. 2023 Aug;81:102625. doi: 10.1016/j.sbi.2023.102625. Epub 2023 Jun 16.
A striking feature of nucleic acids and lipid membranes is that they all carry net negative charge and so is true for the majority of intracellular proteins. It is suggested that the role of this negative charge is to assure a basal intermolecular repulsion that keeps the cytosolic content suitably 'fluid' for function. We focus in this review on the experimental, theoretical and genetic findings which serve to underpin this idea and the new questions they raise. Unlike the situation in test tubes, any functional protein-protein interaction in the cytosol is subject to competition from the densely crowded background, i.e. surrounding stickiness. At the nonspecific limit of this stickiness is the 'random' protein-protein association, maintaining profuse populations of transient and constantly interconverting complexes at physiological protein concentrations. The phenomenon is readily quantified in studies of the protein rotational diffusion, showing that the more net negatively charged a protein is the less it is retarded by clustering. It is further evident that this dynamic protein-protein interplay is under evolutionary control and finely tuned across organisms to maintain optimal physicochemical conditions for the cellular processes. The emerging picture is then that specific cellular function relies on close competition between numerous weak and strong interactions, and where all parts of the protein surfaces are involved. The outstanding challenge is now to decipher the very basics of this many-body system: how the detailed patterns of charged, polar and hydrophobic side chains not only control protein-protein interactions at close- and long-range but also the collective properties of the cellular interior as a whole.
核酸和脂质膜的一个显著特征是它们都带有净负电荷，大多数细胞内蛋白质也是如此。有人认为，这种负电荷的作用是确保基本的分子间斥力，使细胞质内容物保持适当的“流动性”以发挥功能。在这篇综述中，我们关注的是支持这一观点的实验、理论和遗传发现，以及它们提出的新问题。与试管中的情况不同，细胞溶胶中任何功能性的蛋白质-蛋白质相互作用都受到密集拥挤背景（即周围的粘性）的竞争。在这种粘性的非特异性限制下，是“随机”的蛋白质-蛋白质相互作用，在生理蛋白质浓度下保持大量短暂且不断相互转化的复合物。这种现象在蛋白质旋转扩散研究中很容易被量化，表明蛋白质带有的净负电荷越多，其聚集的速度就越慢。进一步证明这种动态的蛋白质-蛋白质相互作用是受进化控制的，并在生物体之间进行精细调节，以维持细胞过程的最佳物理化学条件。然后，出现的情况是，特定的细胞功能依赖于众多弱相互作用和强相互作用之间的紧密竞争，而且蛋白质表面的所有部分都参与其中。目前的挑战是如何解读这个多体系统的基本原理：带电荷、极性和疏水性侧链的详细模式不仅控制着近距离和远距离的蛋白质-蛋白质相互作用，还控制着整个细胞内部的集体性质。
