Structure and function of sialic acids at the plasma membrane

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The membrane of human cells is coated with a heterogenous mixture of carbohydrate structures (glycans) that act as an interface to the external environment and have important structural roles. This structure is often referred to as the 'glycocalyx,' and consists of glycans attached to proteins (glycoproteins) and lipids (glycolipids). Due to the heterogeneous nature of the glycocalyx, our understanding of specific changes that occur at the membrane has been slow to develop. In humans, most extracellular glycans are terminated with sialic acids (Sia) - making this residue an important recognition element for interactions with pathogens, cells, and secreted proteins. ***This proposal describes a research program to advance our understanding of enzymes that process Sia-containing glycans at the plasma membrane, as well as the role of specific Sia-containing structures in cell adhesion and signaling. In Project I, We will build on our expertise in human neuraminidase enzymes (hNEU) by studying activator proteins that alter the specificity of the glycolipid-specific neuraminidase, NEU3. Unusual forms of Sia are found in human cells, these include acetylation at specific hydroxyl groups (OAc-Sia) and polymeric sialic acids (poly-Sia). In Project II, we will develop chemoenzymatic strategies to more efficiently synthesize OAc-Sia and to modify purified complex glycans. In Project III, we will examine the role of human neuraminidase enzymes in the interactions of a class of soluble human proteins known as Galectins. Galectins bind and crosslink cell surface receptors through specific glycan structures that are unmasked by neuraminidase enzymes. In Project IV, we propose to investigate the role of poly-Sia in integrin-mediated cell adhesion using tools developed within our program. Specifically, we will use an isoenzyme of human neuraminidase known to modify poly-Sia, as well as inhibitors of this enzyme that we have previously developed. These studies will reveal the influence of integrin glycosylation on cellular adhesion. ***Together, this program will advance our understanding of Sia glycans in cellular processes and provide new tools for the development of glycoconjugates that could be important components of future vaccines, biologics, or therapeutics.**