Department of Biology, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
Crystallographic Methods, Institute of Molecular Biology of Barcelona-Spanish Research Council, 08028 Barcelona, Spain.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). doi: 10.1073/pnas.2014442118.
Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.
抗菌活性与淀粉样纤维的形成越来越相关，这表明一些人类淀粉样蛋白具有生理作用，而这些淀粉样蛋白在历史上一直被视为严格的病理因子。本研究报告了两栖动物抗菌肽uperin 3.5 的功能性交叉α淀粉样纤维的形成，其结构最初是在细菌 PSMα3 细胞毒素中发现的。uperin 3.5 和 PSMα3 的纤维分别由反平行和平行的螺旋片组成，再现了β-片层的性质。uperin 3.5 表现出二级结构转换的变色龙特性，在没有脂质的情况下主要形成交叉β纤维。uperin 3.5 的螺旋纤维形成主要由细菌细胞或膜类似物诱导，并在其上形成，导致膜损伤和细胞死亡。这些发现表明存在一种调节机制，包括将无活性的肽储存为惰性状态，以及通过变色龙交叉α/β淀粉样纤维，环境诱导 uperin 3.5 的激活。
