In the pituitary gland, hormones are stored in a functional amyloid state within acidic secretory granules before they are released into the blood. To gain a detailed understanding of the structure–function relationship of amyloids in hormone secretion, the three-dimensional (3D) structure of the amyloid fibril of the human hormone β-endorphin was determined by solid-state NMR. We find that β-endorphin fibrils are in a β-solenoid conformation with a protonated glutamate residue in their fibrillar core. During exocytosis of the hormone amyloid the pH increases from acidic in the secretory granule to neutral level in the blood, thus it is suggested—and supported with mutagenesis data—that the pH change in the cellular milieu acts through the deprotonation of glutamate 8 to release the hormone from the amyloid. For amyloid disassembly in the blood, it is proposed that the pH change acts together with a buffer composition change and hormone dilution. In the pituitary gland, peptide hormones can be stored as amyloid fibrils within acidic secretory granules before release into the blood stream. Here, we use solid-state NMR to determine the 3D structure of the amyloid fiber formed by the human hormone β-endorphin. We find that β-endorphin fibrils are in a β-solenoid conformation that is generally reminiscent of other functional amyloids. In the β-endorphin amyloid, every layer of the β-solenoid is composed of a single peptide and protonated Glu8 is located in the fibrillar core. The secretory granule has an acidic pH but, on exocytosis, the β-endorphin fibril would encounter neutral pH conditions (pH 7.4) in the blood; this pH change would result in deprotonation of Glu8 to release the hormone peptide from the amyloid. Analyses of β-endorphin variants carrying mutations in Glu8 support the role of the protonation state of this residue in fibril disassembly, among other environmental changes.

在垂体中，激素在释放到血液中之前以功能性淀粉样蛋白状态储存在酸性分泌颗粒中。为了详细了解淀粉样蛋白在激素分泌中的结构-功能关系，通过固态 NMR 确定了人激素 β-内啡肽的淀粉样原纤维的三维 (3D) 结构。我们发现 β-内啡肽原纤维处于 β-螺线管构象，其原纤维核心中有一个质子化的谷氨酸残基。在激素淀粉样蛋白的胞吐过程中，pH 值从分泌颗粒中的酸性增加到血液中的中性水平，因此建议（并得到诱变数据的支持）细胞环境中的 pH 值变化通过谷氨酸 8 的去质子化作用来释放来自淀粉样蛋白的激素。对于血液中的淀粉样蛋白分解，建议 pH 值变化与缓冲液成分变化和激素稀释一起起作用。在垂体中，肽类激素可以在释放到血流中之前以淀粉样蛋白原纤维的形式储存在酸性分泌颗粒中。在这里，我们使用固态 NMR 来确定由人类激素 β-内啡肽形成的淀粉样纤维的 3D 结构。我们发现 β-内啡肽原纤维处于 β-螺线管构象，这通常让人联想到其他功能性淀粉样蛋白。在 β-内啡肽淀粉样蛋白中，β-螺线管的每一层都由一个肽组成，质子化的 Glu8 位于纤维状核心。分泌颗粒具有酸性 pH 值，但在胞吐作用时，β-内啡肽原纤维会在血液中遇到中性 pH 值条件 (pH 7.4)；这种 pH 变化会导致 Glu8 去质子化，从而从淀粉样蛋白中释放激素肽。对携带 Glu8 突变的 β-内啡肽变体的分析支持该残基的质子化状态在原纤维分解以及其他环境变化中的作用。