title: A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior.
abstract: A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full-length β2-microglobulin. Contrary to the wild-type form, ΔN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ΔN6 amyloidogenesis.
authors.affiliation: Centro de Física da Matéria Condensada & Departamento de Física, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Sílvia G
authors.initials: SG
authors.lastname: Estácio
authors.affiliation: Centro de Física da Matéria Condensada & Departamento de Física, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Krobath
authors.affiliation: Centro de Química e Bioquímica & Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Diogo
authors.initials: D
authors.lastname: Vila-Viçosa
authors.affiliation: Centro de Química e Bioquímica & Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Machuqueiro
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
authors.affiliation: Centro de Física da Matéria Condensada & Departamento de Física, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Patrícia F N
authors.initials: PF
authors.lastname: Faísca
mesh_terms: D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D003198:Computer Simulation; D019281:Dimerization; D008956:Models, Chemical; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D058227:Amyloidogenic Proteins; D046912:Multiprotein Complexes; D001613:beta 2-Microglobulin