Linse Sara, Thalberg Kyrre, Knowles Tuomas P J
Biochemistry and Structural Biology, Chemical Centre, Lund University, Lund, Sweden.
Emmace Consulting, Lund, Sweden.
QRB Discov. 2021 Jul 8;2:e7. doi: 10.1017/qrd.2021.5. eCollection 2021.
Chaperones protect other proteins against misfolding and aggregation, a key requirement for maintaining biological function. Experimental observations of changes in solubility of amyloid proteins in the presence of certain chaperones are discussed here in terms of thermodynamic driving forces. We outline how chaperones can enhance amyloid solubility through the formation of heteromolecular aggregates (co-aggregates) based on the second law of thermodynamics and the flux towards equal chemical potential of each compound in all phases of the system. Higher effective solubility of an amyloid peptide in the presence of chaperone implies that the chemical potential of the peptide is higher in the aggregates formed under these conditions compared to peptide-only aggregates. This must be compensated by a larger reduction in chemical potential of the chaperone in the presence of peptide compared to chaperone alone. The driving force thus relies on the chaperone being very unhappy on its own (high chemical potential), thus gaining more free energy than the amyloid peptide loses upon forming the co-aggregate. The formation of heteromolecular aggregates also involves the kinetic suppression of the formation of homomolecular aggregates. The unhappiness of the chaperone can explain the ability of chaperones to favour an increased population of monomeric client protein even in the absence of external energy input, and with broad client specificity. This perspective opens for a new direction of chaperone research and outlines a set of outstanding questions that aim to provide additional cues for therapeutic development in this area.
伴侣蛋白可保护其他蛋白质免于错误折叠和聚集，这是维持生物学功能的关键要求。本文从热力学驱动力的角度讨论了在某些伴侣蛋白存在下淀粉样蛋白溶解度变化的实验观察结果。我们根据热力学第二定律以及系统各相中每种化合物趋向于相等化学势的通量，概述了伴侣蛋白如何通过形成异分子聚集体（共聚集体）来提高淀粉样蛋白的溶解度。在存在伴侣蛋白的情况下，淀粉样肽具有更高的有效溶解度，这意味着与仅由肽形成的聚集体相比，在这些条件下形成的聚集体中肽的化学势更高。这必须通过与单独存在伴侣蛋白相比，在存在肽的情况下伴侣蛋白化学势的更大降低来补偿。因此，驱动力依赖于伴侣蛋白自身处于非常不稳定的状态（高化学势），从而在形成共聚集体时获得比淀粉样肽损失的更多自由能。异分子聚集体的形成还涉及对同分子聚集体形成的动力学抑制。伴侣蛋白的不稳定状态可以解释即使在没有外部能量输入的情况下，伴侣蛋白也能够有利于增加单体客户蛋白的数量，并且具有广泛的客户特异性。这一观点为伴侣蛋白研究开辟了一个新方向，并概述了一系列突出问题，旨在为该领域的治疗开发提供更多线索。
