The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules  Hao Wu, Monika Fuxreiter  Cell  Volume 165, Issue 5, Pages 1055-1066 (May 2016) DOI: 10.1016/j.cell.2016.05.004 Copyright © 2016 Elsevier Inc. Terms and 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 protein 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. Cell 2016 165, 1055-1066DOI: (10.1016/j.cell.2016.05.004) Copyright © 2016 Elsevier Inc. Terms and Conditions

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. Cell 2016 165, 1055-1066DOI: (10.1016/j.cell.2016.05.004) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 A Schematic Diagram on the Conversion between Different Material States The intrinsically disordered monomer interchanges among many metastable conformations. Transient, motif-mediated interactions that are sampled in the monomer can also be exploited for intermolecular contacts. In liquid droplets, dynamic IDRs enable fuzzy structures with numerous combinations of crosslinking arrangements. A moderate decrease in IDR dynamics, coupled to the increase in contact density, leads to formation of hydrogels. In both these dynamic higher-order assemblies, amyloid-like interactions (N/Q) can be visited but are not stabilized. Once the entropic loss of IDRs reaches a threshold, for example by nucleation, a unidirectional assembly is propagated with very high density of contacts coupled to folding and stabilization of the IDRs, ultimately leading to solid aggregates. LCDs and embedded linear motifs are shown in pink, and two hypothetical folded domains are represented as blue oval and green squares, respectively. Cell 2016 165, 1055-1066DOI: (10.1016/j.cell.2016.05.004) Copyright © 2016 Elsevier Inc. Terms and Conditions