Abstract
Liquid-liquid phase separation (LLPS) explains many intracellular activities, but its role in extracellular functions has not been studied to the same extent. Here we report how LLPS mediates the extracellular function of galectin-3, the only monomeric member of the galectin family. The mechanism through which galectin-3 agglutinates (acting as a “bridge” to aggregate glycosylated molecules) is largely unknown. Our data show that its N-terminal domain (NTD) undergoes LLPS driven by interactions between its aromatic residues (two tryptophans and 10 tyrosines). Our lipopolysaccharide (LPS) micelle model shows that the NTDs form multiple weak interactions to other galectin-3 and then aggregate LPS micelles. Aggregation is reversed when interactions between the LPS and the carbohydrate recognition domains are blocked by lactose. The proposed mechanism explains many of galectin-3’s functions and suggests that the aromatic residues in the NTD are interesting drug design targets.
Highlights
Liquid-liquid phase separation (LLPS) explains many intracellular activities, but its role in extracellular functions has not been studied to the same extent
We demonstrate that galectin-3 LLPS is driven by interactions between aromatic residues in the N-terminal domain (NTD)
As reported previously[33,34,37,38,39,42,47], galectin-3 does not agglutinate in the absence of the NTD (Fig. 1j)
Summary
Liquid-liquid phase separation (LLPS) explains many intracellular activities, but its role in extracellular functions has not been studied to the same extent. Lipid-bound membranes act as compartments that separate reactions (e.g., the synthesis of ATP inside mitochondria; the degradation of proteins inside lysosomes)[1], allowing them to progress efficiently Another mechanism through which biological activities are regulated in cells is the formation of biomolecular condensates ( known as membraneless organelles), such as stress granules, nucleoli, and Cajal bodies[2]. Are some of the most studied examples The multivalency of these proteins is typically the result of repeated amino-acid motifs in intrinsically disordered regions[6], responsible for reversible aggregation and the formation of stress or RNA granules[7,8,9,10]. An accumulation of weak self-associations may promote the formation of higherorder oligomers[51]; how these weak interactions of galectin-3 contribute to stronger interactions such as cell adhesion and signal transduction is unclear
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