Nussinov Ruth, Regev Clil, Jang Hyunbum
Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Cancer Innovation Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
J Mol Biol. 2025 Sep 15:169446. doi: 10.1016/j.jmb.2025.169446.
Allosteric proteins and membrane-less biomolecular condensates are physics-governed pivotal functional components. Allosteric regulation is an inherent physical property of dynamic proteins, and dynamic proteins are allosteric. Thus, in biomolecular condensates (like everywhere else in the cell), allostery is at play, and often missing in condensate descriptions is that the cooperative transitions can involve allosteric effects. The condensate environment can be especially conducive to allostery. Condensed settings can increase the chance of protein interaction and allosteric encounters in function-specific condensates. Specific protein-protein interactions provide the structural framework for signals to transmit cooperatively and dynamically, ultimately modulating cell activity. Their interfaces are commonly enriched in nonpolar (hydrophobic) surface. With abundant functionally specific proteins, and surfaces accommodating multiple hydrophobic patches, interconnected multivalent molecular networks are expected. Lacking hydrophobic cores, disordered proteins' folding-upon-binding scenarios often form strong hydrophobic interfaces, and cooperative (partially disordered) multimers are also common. Repelling water is a major force in condensate formation, albeit not the sole. Here we emphasize dilution as functional and allosteric determinant. Extremely high dilution in rapidly growing proliferating cells can stimulate senescence; lower dilution increases concentration, thus, higher probability of increased proximity and reduced separation, driving protein-protein interactions, and allostery. Is there then effective allostery in condensates? We believe that it depends on the cell state. Under normal physiological conditions, with condensates water content around 40% of total cell mass-yes; over 70% could be too diluted. If too low-it can become function-poor aggregate-like. Effective allostery and signaling require specific interactions, extending from clustered receptors to the cytoskeleton.
变构蛋白和无膜生物分子凝聚物是受物理规律支配的关键功能组件。变构调节是动态蛋白的固有物理特性，而动态蛋白具有变构性。因此，在生物分子凝聚物中（就像细胞中的其他任何地方一样），变构作用在发挥作用，而在凝聚物描述中常常缺失的是协同转变可能涉及变构效应。凝聚物环境可能特别有利于变构作用。凝聚状态可以增加功能特异性凝聚物中蛋白质相互作用和变构相遇的机会。特定的蛋白质 - 蛋白质相互作用为信号协同和动态传递提供了结构框架，最终调节细胞活性。它们的界面通常富含非极性（疏水）表面。由于存在大量功能特异性蛋白质以及容纳多个疏水斑块的表面，预计会形成相互连接的多价分子网络。缺乏疏水核心，无序蛋白的结合折叠情况通常会形成强疏水界面，协同（部分无序）多聚体也很常见。排斥水是凝聚物形成中的主要力量，尽管不是唯一的力量。在这里，我们强调稀释作为功能和变构的决定因素。快速生长的增殖细胞中极高的稀释度会刺激衰老；较低的稀释度会增加浓度，从而增加接近度增加和分离减少的可能性，驱动蛋白质 - 蛋白质相互作用和变构作用。那么凝聚物中存在有效的变构作用吗？我们认为这取决于细胞状态。在正常生理条件下，凝聚物含水量约为细胞总质量的40%时——存在；超过70%可能会过于稀释。如果过低——它可能会变成功能不佳的聚集体样。有效的变构作用和信号传导需要特定的相互作用，从聚集的受体延伸到细胞骨架。
