From selective phases to reversible fibers: context-dependent structural logic of biomolecular condensates

Eukaryotic cellular organization relies on precise compartmentalization. A paradigm shift reveals that proteins with low-complexity domains (LCDs) assemble into dynamic, membraneless compartments called biomolecular condensates. Here, we compare the established “selective phase” model of the nuclear pore complex with the “reversible fiber” concept developed from selected RNA granules, proposing a context-dependent, structure-informed view of macromolecular assembly driven by liquid-liquid phase separation (LLPS). We use the “Temperate Zone” as a descriptive heuristic: in selected systems, LCDs form labile, polymeric assemblies that are sufficiently stable for function yet sufficiently weak for regulation and reversal. This “virtue of weakness” can reflect an evolutionary trade-off, balancing self-assembly with safeguards against pathological transitions. Specific architectures, such as polar zippers and kinked β-sheets, can scaffold selected condensates into viscoelastic network fluids, whereas other condensates remain predominantly disordered and acquire viscoelasticity through transient sticker networks without detectable fibers. Importantly, in some systems, this tunable metastability means environmental stress or mutations can trigger pathological liquid-to-solid transitions, forming toxic aggregates; in other systems, disease can arise from failed condensate formation, altered composition, or depletion of a soluble functional pool. We present a synthesis in which deciphering this “molecular grammar” and the resulting material state is key to understanding condensate formation, physiological function, and dysregulation in condensatopathies such as neurodegeneration and cancer.