A proposed structural model for amyloid fibril elongation: domain swappingforms an interdigitating beta-structure polymer

We propose a model illustrating how proteins, which differ in their overall sequences and structures, can form the propagating, twisted beta -sheet co nformations, characteristic of amyloids, Some cases of amyloid formation ca n be explained through a 'domain swapping' event, where the swapped segment is either a beta -hairpin or an unstable conformation which can partially unfold and assume a beta -hairpin structure. As in domain swapping, here th e swapped beta -hairpin is at the edge of the structure, has few (if any) s alt bridges and hydrogen bonds connecting it to the remainder of the struct ure and variable extents of buried non-polar surface areas. Additionally, i n both cases the swapped piece constitutes a transient 'building block' of the structure, with a high population time. Whereas in domain swapping the swapped fragment has been shown to be an alpha -helix, loop, strand or an e ntire domain, but so far not a beta -hairpin, despite the large number of c ases in which it was already detected, here swapping may involve such a str uctural motif, We show how the swapping of beta -hairpins would form an int erdigitated, twisted beta -sheet conformation, explaining the remarkable hi gh stability of the protofibril in vitro. Such a swapping mechanism is attr active as it involves a universal mechanism in proteins, critical for their function, namely hinge-bending motions. Our proposal is consistent with st ructural superpositioning of mutational variants, While the overall r.m.s.d .s of the wild-type and mutants are small, the proposed hinge-bending regio n consistently shows larger deviations. These larger deviations illustrate that this region is more prone to respond to the mutational changes, regard less of their location in the sequence or in the structure. Nevertheless, a bove all, we stress that this proposition is hypothetical, since it is base d on assumptions lacking definitive experimental support.