Structure of biofilm- forming functional amyloid PSMα1 from aureus

• 成果类型: Article
• 署名作者: Hansen, Kasper Holst; Byeon, Chang Hyeock; Liu, Qian; Drace, Taner; Boesen, Thomas; Conway, James F.; Andreasen, Maria; Akbey, Umit
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Aarhus University; Aarhus University; Aarhus University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13446
• DOI: 10.1073/pnas.2406775121
• 发表日期: 2024-08-13
• 关键词: cryo-em structure; fibrils; peptides; alpha-3

摘要

Biofilm- protected pathogenic Staphylococcus aureus causes chronic infections that are difficult to treat. An essential building block of these biofilms are functional amyloid fibrils that assemble from phenol- soluble modulins (PSMs). PSM alpha 1 cross- seeds other PSMs into cross-beta amyloid folds and is therefore a key element in initiating biofilm formation. However, the paucity of high- resolution structures hinders efforts to prevent amyloid assembly and biofilm formation. Here, we present a 3.5 & Aring; resolution density map of the major PSM alpha 1 fibril form revealing a left- handed cross-beta fibril composed of two C2- symmetric U- shaped protofilaments whose subunits are unusually tilted out- of- plane. Monomeric alpha- helical PSM alpha 1 is extremely cytotoxic to cells, despite the moderate toxicity of the cross-beta fibril. We suggest mechanistic insights into the PSM functional amyloid formation and conformation transformation on the path from monomer- to- fibril formation. Details of PSM alpha 1 assembly and fibril polymorphism suggest how S. aureus utilizes functional amyloids to form biofilms and establish a framework for developing therapeutics against infection and antimicrobial resistance.