The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules

Abstract

We here attempt to achieve an integrated understanding of the structure and dynamics of a number of higher-order assemblies, including amyloids, various kinds of signalosomes, and cellular granules. We propose that the synergy between folded domains, linear motifs, and intrinsically disordered regions regulates the formation and intrinsic fuzziness of all higher-order assemblies, creating a structural and dynamic continuum. We describe how such regulatory mechanisms could be influenced under pathological conditions.

Figure 1. Examples of higher-order assemblies with indicated modes of interactions, roles of IDRs and dynamic properties

(A) The yeast prion Het-s assembles into a triangular β-solenoid amyloid fibril by folding-upon-binding via its C-terminal IDR. (B) The inflammasome adaptor ASC assembles into a filament via the cooperative interactions of its N-terminal PYD. The C-terminal CARDs situate outside the filament to induce downstream caspase-1 recruitment. (C) The p62 autophagy scaffolding protein assembles head-to-tail via its N-terminal PB1 domain to form the main interactions in the filament. The LC3 interacting region and the UBA domain flank outside to mediate their respective interactions. (D) The multivalent protein containing four SH3 domains interacts with another multivalent proteins containing four PRMs to induce phase separation. (E) The RNP granule protein Ddx4 containing multiple short linear motifs undergoes phase separation via weak motif-mediated interactions.

Figure 2. Proposed nucleated polymerization mechanisms in several higher-order systems, with dramatically enhanced local concentrations

(A) Biochemical and structural studies suggest the involvement of two nucleated polymerization steps in the assembly of the AIM2 inflammasome involving the PYDs and the CARDs respectively. To reduce clutter, ASC CARDs are only shown for the ASC subunits at the periphery of the ASC PYD filament, and Caspase-1 Casp domains are only shown for subunits at the periphery of the Caspase-1 filament. (B) A prion oligomer acts as the nucleus to induce the polymerization of the prion monomers. (C) Proposed nucleated polymerization mechanism of a FUS granule in which RNA-bound FUS acts as the nucleus to induce the phase separation of more FUS molecules.

Figure 3. A schematic diagram on the conversion between material states

LCD and embedded linear motifs are shown in pink and two hypothetical folded domains are represented as blue oval and green square respectively.