Centre for Structural Systems Biology, Hamburg, Germany.
Department of Chemistry, University of Hamburg, Hamburg, Germany.
Nat Commun. 2022 Jul 27;13(1):4356. doi: 10.1038/s41467-022-32039-z.
The amyloid-antimicrobial link hypothesis is based on antimicrobial properties found in human amyloids involved in neurodegenerative and systemic diseases, along with amyloidal structural properties found in antimicrobial peptides (AMPs). Supporting this hypothesis, we here determined the fibril structure of two AMPs from amphibians, uperin 3.5 and aurein 3.3, by cryogenic electron microscopy (cryo-EM), revealing amyloid cross-β fibrils of mated β-sheets at atomic resolution. Uperin 3.5 formed a 3-blade symmetrical propeller of nine peptides per fibril layer including tight β-sheet interfaces. This cross-β cryo-EM structure complements the cross-α fibril conformation previously determined by crystallography, substantiating a secondary structure switch mechanism of uperin 3.5. The aurein 3.3 arrangement consisted of six peptides per fibril layer, all showing kinked β-sheets allowing a rounded compactness of the fibril. The kinked β-sheets are similar to LARKS (Low-complexity, Amyloid-like, Reversible, Kinked Segments) found in human functional amyloids.
淀粉样蛋白-抗菌肽假说基于在与神经退行性和系统性疾病相关的人类淀粉样蛋白中发现的抗菌特性，以及在抗菌肽 (AMPs) 中发现的淀粉样蛋白结构特性。支持这一假说，我们通过低温电子显微镜 (cryo-EM) 确定了来自两栖动物的两种 AMPs，uperin 3.5 和 aurein 3.3 的原纤维结构，揭示了在原子分辨率下配对的 β-折叠之间具有交叉-β的纤维。uperin 3.5 形成了三叶对称的三叶桨，每一层原纤维由九个肽组成，包括紧密的β-折叠界面。这种交叉-β cryo-EM 结构补充了以前通过晶体学确定的交叉-α纤维构象，证实了 uperin 3.5 的二级结构转换机制。aurein 3.3 的排列由每一层原纤维的六个肽组成，所有肽都显示出扭曲的 β-折叠，从而使纤维呈圆形紧凑。扭曲的β-折叠类似于在人类功能性淀粉样蛋白中发现的 LARKS（低复杂度、淀粉样样、可逆、扭曲片段）。
