Taylor Jonathan D, Hawthorne William J, Lo Joanne, Dear Alexander, Jain Neha, Meisl Georg, Andreasen Maria, Fletcher Catherine, Koch Marion, Darvill Nicholas, Scull Nicola, Escalera-Maurer Andrés, Sefer Lea, Wenman Rosemary, Lambert Sebastian, Jean Jisoo, Xu Yingqi, Turner Benjamin, Kazarian Sergei G, Chapman Matthew R, Bubeck Doryen, de Simone Alfonso, Knowles Tuomas P J, Matthews Steve J
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Sci Rep. 2016 Apr 21;6:24656. doi: 10.1038/srep24656.
Polypeptide aggregation into amyloid is linked with several debilitating human diseases. Despite the inherent risk of aggregation-induced cytotoxicity, bacteria control the export of amyloid-prone subunits and assemble adhesive amyloid fibres during biofilm formation. An Escherichia protein, CsgC potently inhibits amyloid formation of curli amyloid proteins. Here we unlock its mechanism of action, and show that CsgC strongly inhibits primary nucleation via electrostatically-guided molecular encounters, which expands the conformational distribution of disordered curli subunits. This delays the formation of higher order intermediates and maintains amyloidogenic subunits in a secretion-competent form. New structural insight also reveal that CsgC is part of diverse family of bacterial amyloid inhibitors. Curli assembly is therefore not only arrested in the periplasm, but the preservation of conformational flexibility also enables efficient secretion to the cell surface. Understanding how bacteria safely handle amyloidogenic polypeptides contribute towards efforts to control aggregation in disease-causing amyloids and amyloid-based biotechnological applications.
多肽聚集成淀粉样蛋白与多种使人衰弱的人类疾病相关。尽管存在聚集诱导的细胞毒性的内在风险，但细菌在生物膜形成过程中控制易形成淀粉样蛋白的亚基的输出并组装粘性淀粉样纤维。一种大肠杆菌蛋白CsgC能有效抑制卷曲淀粉样蛋白的淀粉样蛋白形成。在这里，我们揭示了其作用机制，并表明CsgC通过静电引导的分子相互作用强烈抑制初级成核，这扩展了无序卷曲亚基的构象分布。这延迟了高阶中间体的形成，并使淀粉样蛋白生成亚基保持在可分泌的形式。新的结构见解还表明，CsgC是多种细菌淀粉样蛋白抑制剂家族的一部分。因此，卷曲组装不仅在周质中被阻止，而且构象灵活性的保留也使得能够有效地分泌到细胞表面。了解细菌如何安全处理淀粉样蛋白生成多肽有助于控制致病淀粉样蛋白中的聚集以及基于淀粉样蛋白的生物技术应用。
