Figure 1. Schematic highlighting key principles governing discrete, dynamic complexes of IDRs and dynamic, condensed phases of IDRs with exchanging interactions.

(A) Biophysical model for the discrete, dynamic complex formed by Sic1 and the WD40 domain of Cdc4. Multisite phosphorylation of Sic1 (yellow circles) creates numerous weak binding motifs termed Cdc4 phospho-degrons (CPDs) that synergize to yield higher affinity interactions with the positively charged pSer/Thr-Pro pocket (blue-shaded region) of Cdc4. Disorder is retained in the bound state, with transient ordering only around sites of binding. Multiple phosphorylation sites create a mean negative electrostatic field that facilitates retention of pSic1 in the vicinity of Cdc4 (left). Binding of CPDs to the pSer/Thr-Pro binding pocket tethers additional CPDs in close proximity to the weaker affinity allosteric site (purple-shaded region). Negative coupling between the allosteric site and the pSer/Thr-Pro pocket disengages bound CPDs at the pSer/Thr-Pro pocket for subsequent rebinding or dynamic exchange with alternate CPDs (right). Multisite phosphorylation sets a threshold for recognition and elimination of Sic1, leading to precise transition between cell-cycle phases (lower right). (B) Model for the dynamic, bipartite interaction of eIF4E with 4E-BP2. The canonical (⁵⁴YXXXXL⁶⁰) and secondary (⁷⁸IPGVT⁸²) eIF4E-recognition motifs of 4E-BP2 bind to the convex and lateral surfaces of eIF4E, respectively, resulting in the formation of a bipartite interface (left). Significant structural plasticity is retained in the eIF4E-bound state of 4E-BP2, resulting in sampling of heterogeneous conformations (left). On-off exchange dynamics of 4E-BP2 increase accessibility to kinases (left). Phosphorylation induces folding of 4E-BP2 into a 4-stranded β-domain with residues of the canonical binding helix buried in the interior (middle), allowing eIF4G to compete with 4E-BP2 to trigger translation initiation (right). (C) Biophysical model of the intra- and inter-chain dynamics and interactions within the condensed phase of CAPRIN1 C-terminal IDR. Translational diffusion is significantly attenuated in condensed phases of CAPRIN1 LCR, while local chain motions are preserved (top). Local motions facilitate transient contacts between IDR chains with distinct preferences for interactions in certain “hotspot” regions (bottom). The weak, multivalent nature of the interactions allow chains to disengage and reconfigure into different poses that bring various segments of the chains in close proximity as well as enable exchange of interacting chains.