Gerpe Amor, Tania (2024) Physico-chemical Analysis of Siglec-Glycan Complexes. [Tesi di dottorato]

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Abstract

Cells possess glycans at the interface between the environment and the cell membrane. The specific recognition of glycans amongst glycan binding proteins (GBP) triggers many crucial functions, especially in infectious processes, immune responses and inflammation. Siglecs, sialic immunogloblin type lectins, are GBPs that hold critical functions, acting as immune checkpoints through its specific binding with sialic acid. This PhD dissertation tackles some inhibitory Siglecs that downregulate immune cell activation. In detail, Siglec-7, Siglec-9 and Siglec-10, which all contain a V-set domain, one or several C2-Ig domains and their critical tyrosine-based inhibition motifs (ITIMs), have been investigated in the context of disease and therapeutic targets, focusing on their ability to interact with both endogenous and exogenous ligands. Siglec-7, expressed on NK cells, was studied through a multidisciplinary approach, including ligand and protein NMR experiments, fluorescence, ELISA and computational techniques to successfully elucidate the structural and mechanistic aspects of the interactions with pathogenic exogenous ligands. Siglec-9, expressed on leukocytes, primarily engages with endogenous ligands, holding an important role in inflammation and autoimmune diseases. It has been studied through a first comprehensive approach based on computational analysis, to set the basis for a novel therapeutic target for the control of autoimmunity, by engaging immune tolerance. Finally, Siglec-10, expressed on B and dendritic cells, was analyzed in the context of a potential therapeutic target through the study with synthetic and glycomimetics, mimicking natural sialic acids by a first computational approach. Therefore, the molecular details of different Siglecs involving both endogenous and exogenous ligands have been detailed, providing novel insights for the understanding and design of future therapeutic approaches targeting different human diseases.

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