Fig. 5: Current and proposed models for FUS maturation mechanism.

a, Current view of maturation on the macroscopic and atomic levels. b, The proposed model. Fresh droplets have a highly dynamic interface with the solvent allowing protein exchange between phases. Although droplets are initially formed, a fraction of the protein instantaneously adopts a protofibrillar fold that is present both in the bulk of the droplets and on the surface. We propose the existence of a FUS population on the periphery, which because of the unique environment of the interface is not detected in conventional INEPT NMR experiments. Over time, this population is gradually incorporated into the fibrils of the surface. During the fibrilization process the hydrophobic nature of the droplet decreases as the hydrophobic groups of the protein are protected in the fibril core. This increases the flux of solvent molecules inside the droplet causing the diffusivity of the remaining monomers to increase. Once equilibrium is established, the whole surface is converted to fibrillar species resulting in the observed inert hardened shelled, which hinders material exchange between the phases.