Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru, Karnataka560012, India.
J Phys Chem Lett. 2022 Oct 20;13(41):9589-9598. doi: 10.1021/acs.jpclett.2c01972. Epub 2022 Oct 7.
Aggregation of intrinsically disordered proteins (IDPs) can lead to neurodegenerative diseases. Although there is experimental evidence that acidic pH promotes IDP monomer compaction leading to aggregation, the general mechanism is unclear. We studied the pH effect on the conformational ensemble of prothymosin-α (proTα), which is involved in multiple essential functions, and probed its role in aggregation using computer simulations. We show that compaction in the proTα dimension at low pH is due to the protein's collapse in the intermediate region (E41-D80) rich in glutamic acid residues, enhancing its β-sheet content. We observed by performing dimer simulations that the conformations with high β-sheet content could act as aggregation-prone (N*) states and nucleate the aggregation process. The simulations initiated using N* states form dimers within a microsecond time scale, whereas the non-N* states do not form dimers within this time scale. This study contributes to understanding the general principles of pH-induced IDP aggregation.
无序蛋白质（IDPs）的聚集可能导致神经退行性疾病。虽然有实验证据表明酸性 pH 值促进 IDP 单体紧缩导致聚集，但一般机制尚不清楚。我们研究了 pH 值对参与多种基本功能的胸腺肽-α前体（proTα）构象整体的影响，并通过计算机模拟探测其在聚集中的作用。我们表明，低 pH 值下 proTα 尺寸的紧缩是由于富含谷氨酸残基的中间区域（E41-D80）的蛋白质崩溃，从而增强了其β-折叠含量。我们通过进行二聚体模拟观察到，具有高β-折叠含量的构象可以作为易于聚集（N*）状态并引发聚集过程。使用 N状态启动的模拟在微秒时间尺度内形成二聚体，而非 N状态在该时间尺度内不形成二聚体。这项研究有助于理解 pH 诱导 IDP 聚集的一般原则。
