Promiscuous glycan-binding properties of galectin-3 coupled with its dynamic oligomerization can concomitantly activate various signal transduction pathways and, in turn, modulate cell behavior. Modifying the lectin-glycan binding interface to confer signaling pathway selectivity is challenged by the abundance of common carbohydrates that are present on a wide variety of membrane glycoproteins. Alternatively, controlling the multivalent assembly of galectin-3 could provide a physical means to direct its complex extracellular functions. Here, we use a library of α-helical coiled-coils as scaffolds to construct synthetic galectin-3 oligomers with specified valency, and we demonstrate that synthetic galectin-3 assembly can physically regulate membrane glycoprotein recognition to bias the activation of intracellular signaling pathways. Constructs displaying 2-6 galectin-3 subunits (i.e., “Dimer” - “Hexamer”) demonstrated increasing apparent glycan-binding affinity and cell death signaling potency. Though, whereas wild-type galectin-3 signaled caspase-dependent death via CD45 and CD7, Hexamer preferentially signaled death via CD45 due to its abundance and length protruding from the membrane. Preferential engagement of CD45 by Hexamer signaled caspase-independent cell death and diminished caspase-dependent cell activities, such as pannexin-1 hemichannel opening and interleukin-2 secretion, which were more closely associated with wild-type galectin-3 signaling. Therefore, synthetic galectin-3 oligomerization can impart physical control of its carbohydrate-binding promiscuity and, in turn, emergent extracellular functions.

Tuning extracellular galectin-3 signaling using multivalent coiled-coil peptide scaffolds

ACS Spring Meeting 2021

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