The phenol-soluble modulin (PSM) peptide family, secreted by Staphylococcus aureus, performs various virulence activities, some mediated by the formation of amyloid fibrils of diverse architectures. Specifically, PSMα1 and PSMα4 structure the S. aureus biofilm by assembling into robust cross-β amyloid fibrils. PSMα3, the most cytotoxic member of the family, assembles into cross-α fibrils in which α helices stack into tightly mated sheets, mimicking the cross-β architecture. Here we demonstrate that massive T cell deformation and death are linked with PSMα3 aggregation and co-localization with cell membranes. Our extensive mutagenesis analyses support the role of positive charges, and especially Lys17, in interactions with the membrane and suggest their regulation by inter- and intra-helical electrostatic interactions within the cross-α fibril. We hypothesize that PSMα3 cytotoxicity is governed by the ability to form cross-α fibrils and involves a dynamic process of co-aggregation with the cell membrane, rupturing it.

中文翻译：

---

金黄色葡萄球菌PSMα3跨α原纤维多态性和细胞毒性的决定因素。

由金黄色葡萄球菌分泌的酚溶性调节蛋白（PSM）肽家族具有多种毒力活性，其中一些是通过形成多种结构的淀粉样蛋白原纤维来介导的。具体而言，PSMα1和PSMα4通过组装成坚固的交叉β淀粉样蛋白原纤维来构成金黄色葡萄球菌生物膜。PSMα3是家族中最具细胞毒性的成员，可组装成交叉α的原纤维，其中α螺旋堆积成紧密配对的薄片，模仿了交叉β的结构。在这里，我们证明大量的T细胞变形和死亡与PSMα3聚集和细胞膜共定位有关。我们广泛的诱变分析支持正电荷（尤其是Lys17）在与膜的相互作用中的作用，并建议通过交叉α原纤维内部的螺旋间和螺旋内静电相互作用来调节它们。