Why are G-quadruplexes good at preventing protein aggregation?

Maintaining a healthy protein folding environment is essential for cellular function. Recently, we found that nucleic acids, G-quadruplexes in particular, are potent chaperones for preventing protein aggregation. With the aid of structure-function and NMR analyses of two G-quadruplex forming sequences, PARP-I and LTR-III, we uncovered several contributing factors that affect G-quadruplexes in preventing protein aggregation. Notably, three factors emerged as vital in determining holdase activity of G-quadruplexes: their structural topology, G-quadruplex accessibility and dynamics, and oligomerization state. These factors together appear to largely dictate whether a G-quadruplex is able to prevent partially misfolded proteins from aggregating. Understanding the physical traits that govern the ability of G-quadruplexes to modulate protein aggregation will help elucidate their possible roles in neurodegenerative disease.

维持健康的蛋白质折叠环境是细胞发挥正常功能的必要前提。近期我们发现，核酸类物质，尤其是G-四链体（G-quadruplexes），是预防蛋白质聚集的强效分子伴侣。本研究通过对两种G-四链体形成序列PARP-I与LTR-III开展结构-功能分析与核磁共振（NMR）实验，揭示了影响G-四链体预防蛋白质聚集能力的多项关键调控因素。值得注意的是，三大核心因素决定了G-四链体的持留型分子伴侣活性：其结构拓扑构象、G-四链体的可及性与动态特性，以及寡聚化状态。上述因素共同主导了G-四链体能否阻止部分错误折叠蛋白质发生聚集的能力。阐明决定G-四链体调控蛋白质聚集能力的物理特性，将有助于揭示其在神经退行性疾病中可能发挥的作用。