Fig. 2.

Molecular basis of biomolecular phase separation mediated by IDRs and modular domains. Phase separation is facilitated by multivalent interactions among protein domains and motifs, which can be categorized into two primary mechanisms: those mediated by IDRs and those mediated by structured modular domains. IDRs: The sticker–spacer model illustrates how repetitive interaction motifs interspersed with flexible linkers promote multivalent weak interactions, enabling dynamic condensate formation. Alternatively, biomolecular phase separation can occur through scaffold–client systems, where scaffold proteins recruit client proteins via specific binding interfaces to promote phase separation. Modular domains: Structured domain-mediated condensation can arise from self-associating interaction motifs such as SH3–PRM, SUMO–SIM, or multivalent repeats that engage in weak reversible interactions to form mesh-like networks. In contrast, some domains such as DIX, SAM, or PB1 support head-to-tail polymerization, generating linear polymers that undergo phase separation through chain-extension mechanisms