{"title":"疏水塌陷在细胞毒性和功能性淀粉样蛋白寡聚化中的作用。","authors":"Kelsie M King,Hajar Zaheer,Anne M Brown","doi":"10.1016/j.bpj.2025.07.042","DOIUrl":null,"url":null,"abstract":"Amyloid refers to an insoluble, highly organized protein fibril composed of intermolecular β-sheets, known as a cross-β motif. Amyloidogenic proteins are generally driven to aggregate into tightly packed fibrils. Some amyloids are functional, often being utilized as hormone storage reservoirs. The functional, paracrine signaling neuropeptide β-endorphin (βE) is stored and released to modulate pain responses. Conversely, the function of amyloid-β (Aβ), involved in Alzheimer's disease, is uncertain - but substantial evidence exists of its role in neuronal cell apoptosis. While both peptides are mechanistically linked in their propensity to adopt fibrillar structures, the biophysical characteristics that drive divergence in cytotoxic potential are not well understood. To probe the conformational dynamics and mechanisms of functional and cytotoxic oligomer formation, we utilized all-atom molecular dynamics (MD) to simulate the formation of monomeric and hexameric Aβ42 and βE31. Monomeric Aβ42 and βE31 selectively sampled β-strand motifs comprised of hydrophobic residues, adopting a collapsed state. Cluster analysis indicates that βE31 hexamers were more conformationally diverse than those sampled by Aβ42, suggesting βE31 exhibits more signatures of disorder. Aβ42 hexamer formation was driven by hydrophobic packing of collapsed β-strand motifs, where βE31 hexamer peptide subunits remained structurally plastic and solvent accessible. Mutation of Aβ42 disrupting the C-terminal hydrophobic sequence inhibited hydrophobic β-strand formation, reduced aggregation propensity and increased solvent accessibility, suggesting retention of a collapsed state is critical for aberrant oligomer formation. This work provides a preliminary view of cytotoxic and functional oligomer morphologies at atomistic resolution, gaining insights into the biophysical aspects of early aggregation events of amyloids.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"32 1","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The role of hydrophobic collapse in cytotoxic and functional amyloid oligomerization.\",\"authors\":\"Kelsie M King,Hajar Zaheer,Anne M Brown\",\"doi\":\"10.1016/j.bpj.2025.07.042\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Amyloid refers to an insoluble, highly organized protein fibril composed of intermolecular β-sheets, known as a cross-β motif. Amyloidogenic proteins are generally driven to aggregate into tightly packed fibrils. Some amyloids are functional, often being utilized as hormone storage reservoirs. The functional, paracrine signaling neuropeptide β-endorphin (βE) is stored and released to modulate pain responses. Conversely, the function of amyloid-β (Aβ), involved in Alzheimer's disease, is uncertain - but substantial evidence exists of its role in neuronal cell apoptosis. While both peptides are mechanistically linked in their propensity to adopt fibrillar structures, the biophysical characteristics that drive divergence in cytotoxic potential are not well understood. To probe the conformational dynamics and mechanisms of functional and cytotoxic oligomer formation, we utilized all-atom molecular dynamics (MD) to simulate the formation of monomeric and hexameric Aβ42 and βE31. Monomeric Aβ42 and βE31 selectively sampled β-strand motifs comprised of hydrophobic residues, adopting a collapsed state. Cluster analysis indicates that βE31 hexamers were more conformationally diverse than those sampled by Aβ42, suggesting βE31 exhibits more signatures of disorder. Aβ42 hexamer formation was driven by hydrophobic packing of collapsed β-strand motifs, where βE31 hexamer peptide subunits remained structurally plastic and solvent accessible. Mutation of Aβ42 disrupting the C-terminal hydrophobic sequence inhibited hydrophobic β-strand formation, reduced aggregation propensity and increased solvent accessibility, suggesting retention of a collapsed state is critical for aberrant oligomer formation. This work provides a preliminary view of cytotoxic and functional oligomer morphologies at atomistic resolution, gaining insights into the biophysical aspects of early aggregation events of amyloids.\",\"PeriodicalId\":8922,\"journal\":{\"name\":\"Biophysical journal\",\"volume\":\"32 1\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biophysical journal\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.bpj.2025.07.042\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOPHYSICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biophysical journal","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.bpj.2025.07.042","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOPHYSICS","Score":null,"Total":0}
The role of hydrophobic collapse in cytotoxic and functional amyloid oligomerization.
Amyloid refers to an insoluble, highly organized protein fibril composed of intermolecular β-sheets, known as a cross-β motif. Amyloidogenic proteins are generally driven to aggregate into tightly packed fibrils. Some amyloids are functional, often being utilized as hormone storage reservoirs. The functional, paracrine signaling neuropeptide β-endorphin (βE) is stored and released to modulate pain responses. Conversely, the function of amyloid-β (Aβ), involved in Alzheimer's disease, is uncertain - but substantial evidence exists of its role in neuronal cell apoptosis. While both peptides are mechanistically linked in their propensity to adopt fibrillar structures, the biophysical characteristics that drive divergence in cytotoxic potential are not well understood. To probe the conformational dynamics and mechanisms of functional and cytotoxic oligomer formation, we utilized all-atom molecular dynamics (MD) to simulate the formation of monomeric and hexameric Aβ42 and βE31. Monomeric Aβ42 and βE31 selectively sampled β-strand motifs comprised of hydrophobic residues, adopting a collapsed state. Cluster analysis indicates that βE31 hexamers were more conformationally diverse than those sampled by Aβ42, suggesting βE31 exhibits more signatures of disorder. Aβ42 hexamer formation was driven by hydrophobic packing of collapsed β-strand motifs, where βE31 hexamer peptide subunits remained structurally plastic and solvent accessible. Mutation of Aβ42 disrupting the C-terminal hydrophobic sequence inhibited hydrophobic β-strand formation, reduced aggregation propensity and increased solvent accessibility, suggesting retention of a collapsed state is critical for aberrant oligomer formation. This work provides a preliminary view of cytotoxic and functional oligomer morphologies at atomistic resolution, gaining insights into the biophysical aspects of early aggregation events of amyloids.
期刊介绍:
BJ publishes original articles, letters, and perspectives on important problems in modern biophysics. The papers should be written so as to be of interest to a broad community of biophysicists. BJ welcomes experimental studies that employ quantitative physical approaches for the study of biological systems, including or spanning scales from molecule to whole organism. Experimental studies of a purely descriptive or phenomenological nature, with no theoretical or mechanistic underpinning, are not appropriate for publication in BJ. Theoretical studies should offer new insights into the understanding ofexperimental results or suggest new experimentally testable hypotheses. Articles reporting significant methodological or technological advances, which have potential to open new areas of biophysical investigation, are also suitable for publication in BJ. Papers describing improvements in accuracy or speed of existing methods or extra detail within methods described previously are not suitable for BJ.