The three-dimensional structure of human β-endorphin amyloid fibrils
The three-dimensional structure of human β-endorphin amyloid fibrils
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DOI：
10.1038/s41594-020-00515-z
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发表时间：
2020-10-12
影响因子：
16.8
通讯作者：
Riek, Roland
中科院分区：
文献类型：
--
作者：
Seuring, Carolin;Verasdonck, Joeri;Riek, Roland
由人类激素β-内啡肽形成的淀粉样蛋白纤维的固态NMR结构揭示了纤维核心中的质子化Glu 8。在中性条件下，Glu 8的去质子化将促进原纤维的分解和激素肽的释放。在脑垂体中，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-内啡肽的淀粉样蛋白原纤维的三维（3D）结构。我们发现，β-内啡肽纤维是在β-螺线管构象与质子化谷氨酸残基在其纤维核心。在激素淀粉样蛋白的胞吐过程中，pH从分泌颗粒中的酸性增加到血液中的中性水平，因此证实了细胞环境中的pH变化通过谷氨酸8的去质子化作用从淀粉样蛋白中释放激素，并得到诱变数据的支持。对于血液中的淀粉样蛋白分解，提出pH变化与缓冲液组成变化和激素稀释一起起作用。在脑垂体中，肽类激素在释放到血流中之前可以淀粉样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-内啡肽原纤维是在一个β-螺线管构象，这通常是让人想起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单个肽组成，质子化的Glu 8位于纤维核心。分泌颗粒具有酸性pH，但在胞吐作用下，β-内啡肽原纤维将在血液中遇到中性pH条件（pH 7.4）;这种pH变化将导致Glu 8去质子化以从淀粉样蛋白释放激素肽。对携带Glu 8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中的作用，以及其他环境变化。
The solid-state NMR structure of an amyloid fiber formed by human hormone beta-endorphin reveals a protonated Glu8 in the fibrillar core. Under neutral conditions, deprotonation of Glu8 would contribute to fibril disassembly and hormone peptide release.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 beta-endorphin was determined by solid-state NMR. We find that beta-endorphin fibrils are in a beta-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 beta-endorphin. We find that beta-endorphin fibrils are in a beta-solenoid conformation that is generally reminiscent of other functional amyloids. In the beta-endorphin amyloid, every layer of the beta-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 beta-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 beta-endorphin variants carrying mutations in Glu8 support the role of the protonation state of this residue in fibril disassembly, among other environmental changes.