Galectins are a family of proteins that regulate T cell phenotype and function in health and disease via crosslinking and clustering of cell surface glycoproteins. Many galectins mediate these events via dynamic assembly into multivalent quaternary architectures stabilized by weak intermolecular interactions. Here I will present our work using peptides that self-assemble into alpha-helical coiled coils as handles to create synthetic multivalent galectin-glycan signaling constructs. For example, fusing galectin-1 to galectin-3 via a peptide that forms a dimeric alpha-helical coiled-coil provides synthetic tetramers that induce T cell apoptosis with far greater potency than wild-type galectin-1 or galectin-3 alone. This construct activates signaling events by recognizing known glycoprotein receptors of galectin-1 and galectin-3. Enhanced signaling activity arises because the synthetic tetramer having both galectin-1 and galectin-3 domains integrates caspase- and JNK-dependent pro-apoptotic signaling cascades associated with both lectins. Alternatively, fusing galectin-3 to peptides that form alpha-helical coiled-coils with 2-6 strands (i.e., “dimer” through “hexamer”) provides synthetic constructs with user-defined carbohydrate-recognition domain (CRD) valency. Apparent affinity of these synthetic galectin-3 oligomers for immobilized, surface-adsorbed, and cell membrane glycans increases with the number of galectin-3 subunits. Likewise, outside-in signaling mediated by these synthetic galectin-3 oligomers scales with CRD valency. For example, metabolic activity correlates inversely with CRD valency, whereas caspase-3/7 activity and interleukin-2 secretion correlate directly with the number of galectin-3 subunits. Ultimately, these changes in both intracellular and inside-out signaling integrate to afford finely tunable control of the extent of T cell apoptosis. Further, the synthetic hexamer induces a greater extent of T cell death than wild-type galectin-3, suggesting that kinetically trapping CRDs into oligomers with non-natural valency can potentiate galectin-3 signaling. Together, these examples highlight the broad potential of supramolecular peptide scaffolds to modulate glycan-dependent T cell signaling mediate by multivalent galectins. <br/> <br/>

Manipulating multivalent galectin-glycan signaling in T cells using supramolecular peptide scaffolds

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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