Molecular Insight into Glycan Epitopes Recognitionby Host Receptor Proteins

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1st EuroCarb Young Researcher (ECYR) Workshop

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Mini symposium: Glycobiology at the LUMC and beyond

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Molecular Insight into Glycan Epitopes Recognitionby Host Receptor Proteins

Roberta Marchetti 1 , Antonio Molinaro 1 , Alba Silipo 1

1 Department of Chemical Sciences, University of Naples Federico II, Naples, Italy

Glycans display incredible structural diversity (the Glycome) and are involved in fundamental molecular and biological processes, including protein folding, cell-adhesion, molecular trafficking, signal transduction, modulation of receptor activity, as well as many critical functions in immunoregulation and pathological processes (autoimmunity, cancer). The ability of glycans to regulate various aspects of the immune response is mediated by their recognition by various host receptor proteins, including lectins, such as galectins, C-type lectins and Siglecs (Figure 1). Among them, Siglecs are transmembrane receptors that function to recognize ubiquitous sialic acid epitopes on cell surface glycoconjugates, predominantly expressed by innate immune cells. [1] Siglecs are increasingly recognized for their role in helping immune cells to distinguish between “self” and “non-self”, dampening autoimmune responses and controlling inflammation in response to various pathogens. Conversely, many feared pathogens, including membrane-enveloped viruses and bacteria, have the ability to cloak themselves with sialylated glycans that mimic “self’’ allowing them to elude or subvert the host immune responses.[2]

Given that Sialic acid - Siglec interactions have been associated with a broad spectrum of diseases, ranging from autoimmunity to neurodegeneration and cancer, strategies to tune these interactions could have great therapeutic potential.

Within this frame, a multidisciplinary approach, which combines cutting-edge methodologies including advanced ligand-based NMR techniques and computational studies, [3] was applied with the aim to improve our knowledge on the molecular basis of the interaction between functional glycan epitopes and their protein receptors. Our results provide crucial information on different binding mechanisms and represent a key step in the rational design of glycomimetics able to modulate the function of host immune receptor proteins.

Figure 1. Host receptor proteins and the regulation of immune system.

Crocker, PR; Paulson, JC; Varki, A. Nat Rev Immunol. 2007 7, 255.

Büll, C; Heise, T.; Adema, G. J.;, Boltje T. Trends in Biochemical Sciences 2016, 41, 519.

Marchetti, R; Perez, S; Arda, A; Imberty, A; Barbero, J. Jimenez; Silipo, A. Chemistryopen. 2016, 5, 274.

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