title: Visualization of transient protein-protein interactions that promote or inhibit amyloid assembly.
abstract: In the early stages of amyloid formation, heterogeneous populations of oligomeric species are generated, the affinity, specificity, and nature of which may promote, inhibit, or define the course of assembly. Despite the importance of the intermolecular interactions that initiate amyloid assembly, our understanding of these events remains poor. Here, using amyloidogenic and nonamyloidogenic variants of β2-microglobulin, we identify the interactions that inhibit or promote fibril formation in atomic detail. The results reveal that different outcomes of assembly result from biomolecular interactions involving similar surfaces. Specifically, inhibition occurs via rigid body docking of monomers in a head-to-head orientation to form kinetically trapped dimers. By contrast, the promotion of fibrillation involves relatively weak protein association in a similar orientation, which results in conformational changes in the initially nonfibrillogenic partner. The results highlight the complexity of interactions early in amyloid assembly and reveal atomic-level information about species barriers in amyloid formation.
authors: Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors: Theodoros K
authors: TK
authors: Karamanos
authors: Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors: Arnout P
authors: AP
authors: Kalverda
authors: Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors: Gary S
authors: GS
authors: Thompson
authors: Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK. Electronic address: s.e.radford@leeds.ac.uk.
authors: Sheena E
authors: SE
authors: Radford
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics
chemical_list: D000682:Amyloid; D001613:beta 2-Microglobulin