Salt Bridges Regulate in Silico Dimers Formation for β2-Microglobulin Amyloidogenic Variants
Abstract
β2-microglobulin is a paradigmatic amyloidogenic protein responsible fordialysis-related amyloidosis, a disease associated to long-term hemodialyzedpatients and characterized by accumulation of amyloid deposits in the osteoar-ticular tissues. In the early stages of amyloid fibril formation, β2-microglobulinassociates into dimers and higher oligomers, but clarifications are still neededfor the triggering conditions, mechanisms and specificity of dimer forma-tion. To characterize the dimeric association process, the protein-proteininteractions between three different species are investigated: namely, thenative protein and the two amyloidogenic variants ΔN6 and D76N. Thedimerization process is rationalized relying on state of the art computationalmethods. A comparative mechanism for how different mutations in the threevariants can affect protein dimerization and thus fibril formation is proposed. The number of salt bridges involved at the protein-protein interface correlateswith the degree of amyloidogenicity of each individual species. The findingscan offer possible strategies in controlling the dimerization mechanism basedon different β2-microglobulin protein mutations, which have significant rolesin the fibrillogenical process.
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