Mechanistic overview of protein-specific polysialylation

Polysialic acid is a polymer of α2,8-linked sialic acid residues attached to the termini of glycans that modify a select group of glycoproteins. It plays repulsive and attractive roles in nervous system and immune cell development and function, as well as cancer cell survival and metastasis and tissue regeneration, by negatively modulating the interactions of cells and proteins and by acting as a binding site to sequester biologically active molecules, respectively. An abundance of literature has shown that polysialylation is a protein-specific process in that the polysialyltransferases (polySTs) recognize and bind to sequences in one region of a protein substrate, which then allows them to polysialylate glycans in an adjacent region of that protein substrate. In this review, the requirements for the polysialylation of the neural cell adhesion molecule, synaptic cell adhesion molecule 1, and neuropilin 2 are discussed. The identification of acidic glycoprotein substrate sequences and corresponding basic polyST sequences that mediate the substrate-enzyme interaction is described, evidence for the direct interaction of these sequences in the case of the neural cell adhesion molecule is provided, conserved residues that may form a basic groove on the polyST surface that promotes polysialic acid chain polymerization are identified, and the role of polyST autopolysialylation in promoting glycoprotein substrate polysialylation is discussed. Finally, a perspective on how this information might be used to devise approaches to block or enhance polysialylation for therapeutic purposes is offered.