Division of Physical Chemistry, Department of Chemistry, Lund University, 22100 Lund, Sweden;
Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2020 May 12;117(19):10113-10121. doi: 10.1073/pnas.1914599117. Epub 2020 Apr 13.
Cellular function is generally depicted at the level of functional pathways and detailed structural mechanisms, based on the identification of specific protein-protein interactions. For an individual protein searching for its partner, however, the perspective is quite different: The functional task is challenged by a dense crowd of nonpartners obstructing the way. Adding to the challenge, there is little information about how to navigate the search, since the encountered surrounding is composed of protein surfaces that are predominantly "nonconserved" or, at least, highly variable across organisms. In this study, we demonstrate from a colloidal standpoint that such a blindfolded intracellular search is indeed favored and has more fundamental impact on the cellular organization than previously anticipated. Basically, the unique polyion composition of cellular systems renders the electrostatic interactions different from those in physiological buffer, leading to a situation where the protein net-charge density balances the attractive dispersion force and surface heterogeneity at close range. Inspection of naturally occurring proteomes and in-cell NMR data show further that the "nonconserved" protein surfaces are by no means passive but chemically biased to varying degree of net-negative repulsion across organisms. Finally, this electrostatic control explains how protein crowding is spontaneously maintained at a constant level through the intracellular osmotic pressure and leads to the prediction that the "extreme" in halophilic adaptation is not the ionic-liquid conditions per se but the evolutionary barrier of crossing its physicochemical boundaries.
细胞功能通常在功能途径和详细结构机制的层面上进行描述，这是基于对特定蛋白质-蛋白质相互作用的识别。然而，对于单个蛋白质来说，其寻找伴侣的视角则完全不同：功能性任务受到密集的非伴侣群体的阻碍。更具挑战性的是，由于遇到的周围环境主要由“非保守”或至少在生物体之间高度可变的蛋白质表面组成，因此关于如何进行搜索的信息很少。在这项研究中，我们从胶体的角度证明，这种盲目搜索实际上是有利的，并且对细胞组织的影响比以前预期的更为深远。基本上，细胞系统独特的聚离子组成使静电相互作用与生理缓冲液中的静电相互作用不同，导致蛋白质净电荷密度在近距离平衡吸引力分散力和表面异质性。对天然存在的蛋白质组和细胞内 NMR 数据的进一步检查表明，“非保守”蛋白质表面绝非被动的，而是在不同程度上受到化学偏置的影响，具有净负排斥性，跨越生物体。最后，这种静电控制解释了为什么蛋白质拥挤可以通过细胞内渗透压自发地维持在一个恒定的水平，并预测了“极端”嗜盐适应的不是离子液体条件本身，而是跨越其物理化学边界的进化障碍。
