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Multivalent Carbohydrates As New and Powerful Probes of Signal Transduction

The ability of polymers generated by ROMP to cluster proteins prompted us to examine their utility for activating signal transduction. Multiprotein complexes are the critical mediators of signal transduction. We created multifunctional ligands to direct the formation of multiprotein complexes (Fig. 3). Such ligands, which can be used like small molecules for temporal control, can illuminate how protein assembly regulates cellular responses. For example, we used carbohydrate-based multivalent attractants to reveal how bacteria sense attractants and repellents. We found that a single receptor type is not sufficient to sense a specific attractant – an array of receptors is required for proper sensing and movement toward attractants. In effect, the clustered receptors act as a type of sensory organ (nose) that allow bacteria to respond sensitively and appropriately to stimuli in the environment (12, 17). We have recently created multifunctional compounds that can co-cluster multiple copies of a carbohydrate-binding protein with copies of another signaling receptor (Fig 3). We synthesized compounds that promote the formation of specific multiprotein complexes to down-regulate signaling on immune cells (18). Thus, we can use our knowledge of synthetic chemistry and the cellular building blocks to assemble complexes that augment immune responses (for vaccine development) or attenuate them (for treatment of autoimmune diseases).

Fig 3. Schematic depiction of how multivalent ligands can cluster multiple types of proteins. Left: Multivalent compounds with only one group (blue) can cluster the B cell receptor (BCR, blue) and activate B cells of the immune system to lead to antibody production. Right: Multivalent compounds (blue and red) that can co-cluster two receptors (CD22 and the BCR) downregulate immune responses. Compounds like this could help treat autoimmune diseases.

12. Gestwicki JE, Kiessling LL. Inter-receptor communication through arrays of bacterial chemoreceptors. Nature. 2002;415(6867):81-4. 

17. Borrok MJ, Kolonko EM, Kiessling LL. Chemical probes of bacterial signal transduction reveal that repellents stabilize and attractants destabilize the chemoreceptorarray. ACS Chem Biol. 2008;3(2):101-9. 

18. Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation. Proc Natl Acad Sci U S A. 2009;106(8):2500-5.