Staphylococcus aureus phenol soluble modulin aggregation kinetics

The infective ability of the opportunistic pathogen Staphylococcus aureus, recognized as the most frequent cause of biofilm-associated infections, is associated with biofilm mediated resistance to host immune response. Phenol-soluble modulins (PSM) comprise the structural scaffold of S. aureus biofilms through self-assembly into functional amyloids, but the role of individual PSMs during biofilm formation remains poorly understood and the molecular pathways of PSM self-assembly have yet to be identified. Here, we demonstrate high degree of cooperation between individual PSMs during functional amyloid formation. PSMα3 initiates the aggregation, forming unstable aggregates capable of seeding other PSMs resulting in stable amyloid structures. Using chemical kinetics we dissect the molecular mechanism of aggregation of individual PSMs showing that PSMα1, PSMα3 and PSMβ1 display secondary nucleation whereas PSMβ2 aggregates through primary nucleation and elongation. Our findings suggest that...作为生物膜相关感染最常见致病菌的机会致病菌金黄色葡萄球菌（Staphylococcus aureus），其感染能力与其生物膜介导的宿主免疫应答抗性紧密相关。酚溶性调控蛋白（Phenol-soluble modulins, PSM）可通过自组装形成功能性淀粉样蛋白，构成金黄色葡萄球菌生物膜的结构骨架，但单个PSM在生物膜形成过程中的具体作用仍未被充分阐明，且PSM自组装的分子通路尚未得到明确鉴定。本研究证实，单个PSM在功能性淀粉样蛋白形成过程中存在高度协同效应：PSMα3可启动聚集过程，形成不稳定聚集体并可作为晶种诱导其他PSM聚集，最终生成稳定的淀粉样蛋白结构。本研究借助化学动力学分析解析了单个PSM的聚集分子机制，结果显示PSMα1、PSMα3与PSMβ1均存在二次成核现象，而PSMβ2则通过一次成核与延伸途径完成聚集。本研究结果表明……