Proteins function in the crowded cellular environments with high salt concentrations, thus facing tremendous challenges of misfolding/aggregation which represents a pathological hallmark of aging and an increasing spectrum of human diseases. Recently, intrinsically disordered regions (IDRs) were recognized to drive liquid–liquid phase separation (LLPS), a common principle for organizing cellular membraneless organelles (MLOs). ATP, the universal energy currency for all living cells, mysteriously has concentrations of 2–12 mM, much higher than required for its previously-known functions. Only recently, ATP was decoded to behave as a biological hydrotrope to inhibit protein LLPS and aggregation at mM. We further revealed that ATP also acts as a bivalent binder, which not only biphasically modulates LLPS driven by IDRs of human and viral proteins, but also bind to the conserved nucleic-acid-binding surfaces of the folded proteins. Most unexpectedly, ATP appears to act as a hydration mediator to antagonize the crowding-induced destabilization as well as to enhance folding of proteins without significant binding. Here, this review focuses on summarizing the results of these biophysical studies and discussing their implications in an evolutionary context. By linking triphosphate with unique hydration property to adenosine, ATP appears to couple the ability for establishing hydrophobic, π-π, π-cation and electrostatic interactions to the capacity in mediating hydration of proteins, which is at the heart of folding, dynamics, stability, phase separation and aggregation. Consequently, ATP acquired a category of functions at ~mM to energy-independently control protein homeostasis with diverse mechanisms, thus implying a link between cellular ATP concentrations and protein-aggregation diseases.

中文翻译：

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三磷酸腺苷具有独特的结构和多样的机制，能量独立地控制蛋白质稳态


蛋白质在高盐浓度的拥挤细胞环境中发挥作用，因此面临着错误折叠/聚集的巨大挑战，这是衰老和不断增加的人类疾病的病理标志。最近，本质无序区域（IDR）被认为可以驱动液-液相分离（LLPS），这是组织细胞无膜细胞器（MLO）的共同原理。 ATP 是所有活细胞的通用能量货币，其浓度神秘地为 2-12 mM，远高于其先前已知功能所需的浓度。直到最近，ATP 才被解码为生物水溶助长剂，可抑制蛋白质 LLPS 和 mM 聚集。我们进一步发现，ATP 还充当二价结合剂，它不仅双相调节由人类和病毒蛋白的 IDR 驱动的 LLPS，而且还与折叠蛋白的保守核酸结合表面结合。最出乎意料的是，ATP 似乎充当水合介体，以对抗拥挤引起的不稳定，并在没有显着结合的情况下增强蛋白质的折叠。在这里，这篇综述的重点是总结这些生物物理学研究的结果，并讨论它们在进化背景下的含义。通过将具有独特水合特性的三磷酸与腺苷连接，ATP 似乎将建立疏水性、π-π、π-阳离子和静电相互作用的能力与介导蛋白质水合的能力结合起来，这是折叠、动力学、稳定性的核心，相分离和聚集。 因此，ATP 在~mM 下获得了一类功能，以不同的机制独立于能量控制蛋白质稳态，从而暗示细胞 ATP 浓度与蛋白质聚集疾病之间的联系。