Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.
Curr Protein Pept Sci. 2020;21(1):3-21. doi: 10.2174/1389203720666190725114550.
Proteins can undergo kinetic/thermodynamic partitioning between folding and aggregation. Proper protein folding and thermodynamic stability are crucial for aggregation inhibition. Thus, proteinfolding principles have been widely believed to consistently underlie aggregation as a consequence of conformational change. However, this prevailing view appears to be challenged by the ubiquitous phenomena that the intrinsic and extrinsic factors including cellular macromolecules can prevent aggregation, independently of (even with sacrificing) protein folding rate and stability. This conundrum can be definitely resolved by 'a simple principle' based on a rigorous distinction between protein folding and aggregation: aggregation can be controlled by affecting the intermolecular interactions for aggregation, independently of the intramolecular interactions for protein folding. Aggregation is beyond protein folding. A unifying model that can conceptually reconcile and underlie the seemingly contradictory observations is described here. This simple principle highlights, in particular, the importance of intermolecular repulsive forces against aggregation, the magnitude of which can be correlated with the size and surface properties of molecules. The intermolecular repulsive forces generated by the common intrinsic properties of cellular macromolecules including chaperones, such as their large excluded volume and surface charges, can play a key role in preventing the aggregation of their physically connected polypeptides, thus underlying the generic intrinsic chaperone activity of soluble cellular macromolecules. Such intermolecular repulsive forces of bulky cellular macromolecules, distinct from protein conformational change and attractive interactions, could be the puzzle pieces for properly understanding the combined cellular protein folding and aggregation including how proteins can overcome their metastability to amyloid fibrils in vivo.
蛋白质可以在折叠和聚集之间发生动力学/热力学分配。正确的蛋白质折叠和热力学稳定性对于抑制聚集至关重要。因此，人们普遍认为蛋白质折叠原理一直是聚集的基础，这是构象变化的结果。然而，这种主流观点似乎受到无处不在的现象的挑战，即包括细胞大分子在内的内在和外在因素可以独立于（甚至牺牲）蛋白质折叠速率和稳定性来防止聚集。这个难题可以通过基于对蛋白质折叠和聚集的严格区分的“简单原理”来解决：可以通过影响聚集的分子间相互作用来控制聚集，而不影响蛋白质折叠的分子内相互作用。聚集超越了蛋白质折叠。这里描述了一个统一的模型，可以从概念上协调并支持看似矛盾的观察结果。这个简单的原理特别强调了抗聚集的分子间斥力的重要性，其大小可以与分子的大小和表面特性相关联。细胞大分子（包括伴侣蛋白）的常见内在特性产生的分子间斥力，如它们的大排除体积和表面电荷，可以在防止与其物理连接的多肽聚集方面发挥关键作用，从而为可溶性细胞大分子的一般内在伴侣活性提供了基础。这种不同于蛋白质构象变化和吸引力的细胞大分子的分子间斥力，可能是正确理解包括蛋白质如何在体内克服其亚稳性形成淀粉样纤维在内的细胞蛋白质折叠和聚集的关键拼图。
