Laura Bonnecaze, Katlyn Jumel, Anthony Vial, Lucie Khemtemourian, Cécile Feuillie, Michael Molinari, Sophie Lecomte and Marion Mathelié-Guinlet
{"title":"N-Formylation modifies membrane damage associated with PSMα3 interfacial fibrillation†","authors":"Laura Bonnecaze, Katlyn Jumel, Anthony Vial, Lucie Khemtemourian, Cécile Feuillie, Michael Molinari, Sophie Lecomte and Marion Mathelié-Guinlet","doi":"10.1039/D4NH00088A","DOIUrl":null,"url":null,"abstract":"<p >The virulence of <em>Staphylococcus aureus</em>, a multi-drug resistant pathogen, notably depends on the expression of the phenol soluble modulins α3 (PSMα3) peptides, able to self-assemble into amyloid-like cross-α fibrils. Despite remarkable advances evidencing the crucial, yet insufficient, role of fibrils in PSMα3 cytotoxic activities towards host cells, the relationship between its molecular structures, assembly propensities, and modes of action remains an open intriguing problem. In this study, combining atomic force microscopy (AFM) imaging and infrared spectroscopy, we first demonstrated <em>in vitro</em> that the charge provided by the N-terminal capping of PSMα3 alters its interactions with model membranes of controlled lipid composition without compromising its fibrillation kinetics or morphology. N-formylation eventually dictates PSMα3-membrane binding <em>via</em> electrostatic interactions with the lipid head groups. Furthermore, PSMα3 insertion within the lipid bilayer is favoured by hydrophobic interactions with the lipid acyl chains only in the fluid phase of membranes and not in the gel-like ordered domains. Strikingly, our real-time AFM imaging emphasizes how intermediate protofibrillar entities, formed along PSMα3 self-assembly and promoted at the membrane interface, likely disrupt membrane integrity <em>via</em> peptide accumulation and subsequent membrane thinning in a peptide concentration and lipid-dependent manner. Overall, our multiscale and multimodal approach sheds new light on the key roles of N-formylation and intermediate self-assembling entities, rather than mature fibrils, in dictating deleterious interactions of PSMα3 with membrane lipids, likely underscoring its ultimate cellular toxicity <em>in vivo</em>, and in turn <em>S. aureus</em> pathogenesis.</p>","PeriodicalId":93,"journal":{"name":"Nanoscale Horizons","volume":null,"pages":null},"PeriodicalIF":8.0000,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/nh/d4nh00088a?page=search","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nanoscale Horizons","FirstCategoryId":"88","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/nh/d4nh00088a","RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
引用次数: 0
Abstract
The virulence of Staphylococcus aureus, a multi-drug resistant pathogen, notably depends on the expression of the phenol soluble modulins α3 (PSMα3) peptides, able to self-assemble into amyloid-like cross-α fibrils. Despite remarkable advances evidencing the crucial, yet insufficient, role of fibrils in PSMα3 cytotoxic activities towards host cells, the relationship between its molecular structures, assembly propensities, and modes of action remains an open intriguing problem. In this study, combining atomic force microscopy (AFM) imaging and infrared spectroscopy, we first demonstrated in vitro that the charge provided by the N-terminal capping of PSMα3 alters its interactions with model membranes of controlled lipid composition without compromising its fibrillation kinetics or morphology. N-formylation eventually dictates PSMα3-membrane binding via electrostatic interactions with the lipid head groups. Furthermore, PSMα3 insertion within the lipid bilayer is favoured by hydrophobic interactions with the lipid acyl chains only in the fluid phase of membranes and not in the gel-like ordered domains. Strikingly, our real-time AFM imaging emphasizes how intermediate protofibrillar entities, formed along PSMα3 self-assembly and promoted at the membrane interface, likely disrupt membrane integrity via peptide accumulation and subsequent membrane thinning in a peptide concentration and lipid-dependent manner. Overall, our multiscale and multimodal approach sheds new light on the key roles of N-formylation and intermediate self-assembling entities, rather than mature fibrils, in dictating deleterious interactions of PSMα3 with membrane lipids, likely underscoring its ultimate cellular toxicity in vivo, and in turn S. aureus pathogenesis.
期刊介绍:
Nanoscale Horizons stands out as a premier journal for publishing exceptionally high-quality and innovative nanoscience and nanotechnology. The emphasis lies on original research that introduces a new concept or a novel perspective (a conceptual advance), prioritizing this over reporting technological improvements. Nevertheless, outstanding articles showcasing truly groundbreaking developments, including record-breaking performance, may also find a place in the journal. Published work must be of substantial general interest to our broad and diverse readership across the nanoscience and nanotechnology community.