Emergent functional structures in membrane signaling: Higher-order transient structures and their biomolecular condensate phase

Many biological functions emerge from collections of interacting molecules. In particular, recent data suggest that many membrane signaling processes rely on an inherently stochastic, highly dynamic form of biochemical organization named higher-order transient structures (HOTS). HOTS function, for instance, as 10 - 100 nanometer sized, transient hubs of membrane signaling in G protein pathways. We describe the general physical principles underlying HOTS self-assembly, the thermodynamic relationship between HOTS and biomolecular condensates, and potential roles of HOTS in biology stemming from their unique physical characteristics. Currently, a quantitative physical understanding of HOTS is limited to membrane proteins. But many observations suggest that HOTS are also abundant in three-dimensional cellular compartments, and more broadly underlie the connectivity of molecular components in signaling pathways, metabolic pathways, and other forms of dynamic structure and function transcending single biomolecules.