Fig. 6: Models for primary and secondary nucleation.

a, Disordered parts of the molecules are shown in grey; other colours represent ordered structures, with the same colours as in Fig. 4. Primary nucleation (pink arrow) of disordered monomers with partially rigid β-strands may lead to formation of the FIA. Subsequent secondary nucleation (grey arrows) may then occur through folding back of the carboxy-terminal domain of tau monomers at the end of, or at defects in, the FIA to form the interface between residues 305–316 and 370–380 that remains nearly constant in all intermediate and final filament types. This folding back may then lead to the seed of an early J-shaped protofilament. Possibly, the formation of singlets of J-shaped protofilaments (as observed in the CTE reaction) is followed by packing of a second protofilament to form more stable doublets. b, Secondary nucleation by sliding of protofilaments relative to each other (indicated with small black arrows), again at the ends of, or at defects in, filaments may lead to the subsequent formation of more stable structures. c, Alternatively, secondary nucleation through the addition and removal of protofilaments may happen when more stable protofilament interactions form at the sides of existing filaments. d, Secondary nucleation through conformational change may lead to protofilament maturation, from early J-shaped protofilaments to later C-shaped protofilaments, again at the end of, or at defects in, filaments. e, Secondary nucleation through the splitting of filaments may lead to two smaller filament types (for example, Extended Data Fig. 3f). Combined with secondary nucleation through the addition and removal of protofilaments, this may lead to an interplay between multiple filament types.