Choi Seong Il, Jin Yoontae, Choi Yura, Seong Baik L
Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Vaccine Innovative Technology ALliance (VITAL)-Korea, Seoul 03722, Republic of Korea.
Int J Mol Sci. 2024 Dec 24;26(1):53. doi: 10.3390/ijms26010053.
Aggregation is intricately linked to protein folding, necessitating a precise understanding of their relationship. Traditionally, aggregation has been viewed primarily as a sequential consequence of protein folding and misfolding. However, this conventional paradigm is inherently incomplete and can be deeply misleading. Remarkably, it fails to adequately explain how intrinsic and extrinsic factors, such as charges and cellular macromolecules, prevent intermolecular aggregation independently of intramolecular protein folding and structure. The pervasive inconsistencies between protein folding and aggregation call for a new framework. In all combined reactions of molecules, both intramolecular and intermolecular rate (or equilibrium) constants are mutually independent; accordingly, intrinsic and extrinsic factors independently affect both rate constants. This universal principle, when applied to protein folding and aggregation, indicates that they should be treated as two independent yet interconnected processes. Based on this principle, a new framework provides groundbreaking insights into misfolding, Anfinsen's thermodynamic hypothesis, molecular chaperones, intrinsic chaperone-like activities of cellular macromolecules, intermolecular repulsive force-driven aggregation inhibition, proteome solubility maintenance, and proteinopathies. Consequently, this paradigm shift not only refines our current understanding but also offers a more comprehensive view of how aggregation is coupled to protein folding in the complex cellular milieu.
聚集与蛋白质折叠紧密相连，因此需要精确理解它们之间的关系。传统上，聚集主要被视为蛋白质折叠和错误折叠的后续结果。然而，这种传统范式本质上是不完整的，可能会产生严重误导。值得注意的是，它无法充分解释诸如电荷和细胞大分子等内在和外在因素如何独立于分子内蛋白质折叠和结构来防止分子间聚集。蛋白质折叠和聚集之间普遍存在的不一致性需要一个新的框架。在分子的所有组合反应中，分子内和分子间的速率（或平衡）常数相互独立；因此，内在和外在因素独立地影响这两个速率常数。这一普遍原则应用于蛋白质折叠和聚集时，表明它们应被视为两个独立但相互关联的过程。基于这一原则，一个新的框架为错误折叠、安芬森热力学假说、分子伴侣、细胞大分子的内在伴侣样活性、分子间排斥力驱动的聚集抑制、蛋白质组溶解度维持和蛋白质病提供了开创性的见解。因此，这种范式转变不仅完善了我们目前的理解，还提供了一个更全面的视角，以了解在复杂的细胞环境中聚集如何与蛋白质折叠相耦合。
