Insulin has long been served as a model for protein aggregation, both due to the importance of aggregation in the manufacture of insulin and because the structural biology of insulin has been extensively characterized. Despite intensive study, details about the initial triggers for aggregation have remained elusive at the molecular level. We show here that at acidic pH, the aggregation of insulin is likely initiated by a partially folded monomeric intermediate. High‐resolution structures of the partially folded intermediate show that it is coarsely similar to the initial monomeric structure but differs in subtle details—the A chain helices on the receptor interface are more disordered and the B chain helix is displaced from the C‐terminal A chain helix when compared to the stable monomer. The result of these movements is the creation of a hydrophobic cavity in the center of the protein that may serve as nucleation site for oligomer formation. Knowledge of this transition may aid in the engineering of insulin variants that retain the favorable pharamacokinetic properties of monomeric insulin but are more resistant to aggregation.

中文翻译：

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部分折叠的胰岛素聚集中间体的高分辨率结构。

由于聚集在胰岛素生产中的重要性以及胰岛素的结构生物学已被广泛表征，胰岛素长期以来一直是蛋白质聚集的模型。尽管进行了深入的研究，但在分子水平上仍不清楚关于聚集的初始诱因的细节。我们在这里表明在酸性pH值下，胰岛素的聚集很可能是由部分折叠的单体中间体引发的。部分折叠的中间体的高分辨率结构显示，它与初始单体结构大致相似，但细节上有所不同-受体界面上的A链螺旋更无序，B链螺旋从C端A移位与稳定单体相比，链螺旋。这些运动的结果是在蛋白质中心形成疏水腔，该疏水腔可用作寡聚体形成的成核位点。对该转变的了解可能有助于工程改造胰岛素变体，这些变体保留了单体胰岛素的有利相动力学特性，但更不易聚集。