Fig. 1: Secondary nucleation is a core process driving amyloid fibril proliferation; however, its structural basis is not understood.

a Overall reaction network governing amyloid fibril formation. Secondary nucleation is often responsible for most new fibril formation. b Possible ways amyloid fibrils might promote secondary nucleation of new fibrils (and oligomers). (i): Uniform catalysis of nucleation across the entire fibril surface. (ii): Rare super-spreader fibrils have dense catalytic sites, with most fibrils being incapable of promoting secondary nucleation. (iii): Secondary nucleation sites are defects in the fibril core, created during fibril elongation. Such defects can coincide with dislocations or branches (LHS, and bottom row), although non-offset defect structures are also possible (RHS). Dark and light blue colours distinguish separate protofilaments. Fibril cross-sections denoted by purple units and marked by arrows are exposed at dislocation or branching defect sites. The fraction of monomer units exposed may differ from that illustrated here. For simplicity, defects in subsequent figures will be represented schematically as dislocations only.