Helical epitope of the group B meningococcal .alpha.(2-8)-linked sialic acid polysaccharide

Abstract

The immunological properties of the group B meningococcal alpha(2-8)-linked sialic acid polysaccharide have been rationalized in terms of a model where the random coil nature of the polymer can be described by the presence of local helices. The conformational versatility of the alpha NeuAc(2-8)alpha NeuAc linkage has been explored by NMR studies at 600 MHz in conjunction with potential energy calculations for colominic acid, an alpha(2-8)NeuAc polymer, and the trisaccharide alpha NeuAc(2-8)alpha NeuAc(2-8)beta NeuAc. Potential energy calculations were used to estimate the energetically favorable conformers and to describe the wide range of helices which the polymer can adopt. No unique conformer was found to satisfy all NMR constraints, and only ensemble averaged nuclear Overhauser enhancements could correctly simulate the experimental data. Conformational differences between the polymer and the trisaccharide could be best explained in terms of slight changes in the relative distribution of conformers in solution. Similar helical parameters for the alpha(2-8)NeuAc polymer and poly(A) were proposed as the basis for their cross-reactivity to a monoclonal antibody IgMNOV. The unusual length dependency for binding of oligosaccharide to group B specific antibodies was postulated to arise from the recognition of a high-order local helix with an extended conformation which was not highly populated in solution.

Crystal Structure of Anti-polysialic Acid Antibody Single Chain Fv Fragment Complexed with Octasialic Acid

“…The conformations of the trisialic acids in the two antigenbinding sites are essentially identical. The dihedral angles of a helical conformation reported in a previous docking model study are Ϫ45°, 130°, 60°, and 60°, respectively (14). In this structure, however, the dihedral angles of the interacting trisialic acid demonstrate a rather unfolded conformation and differ greatly from those mentioned above for the proposed helical conformation (underlined in Table 3).…”

“…Flexible helical structures were suggested by nuclear magnetic resonance (NMR) analyses with the aid of molecular modeling and dynamics calculations. Two groups independently reported helical structures, but the pitches of the proposed helices are significantly different (13,14). More recently, another helical structure was suggested based on trisialic acid analysis using high field NMR with molecular dynamics simulations (15).…”

Ligands for the β-Glucan Receptor, Dectin-1, Assigned Using “Designer” Microarrays of Oligosaccharide Probes (Neoglycolipids) Generated from Glucan Polysaccharides

“…The requirement of Dectin-1 for decasaccharides or longer oligosaccharides of glucans is reminiscent of the properties of antibodies specific for another homo-oligomer, ␣2-8-linked polysialic acid. NMR studies together with potential energy calculations led to the postulate that the unusual oligosaccharide length dependence for recognition by these antibodies arises from the existence of a conformational epitope, a high order local helix (37).…”

Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane

“…Similar to MARCKS, it has been shown that PSA associates with liposomal membranes and penetrates lipid bilayers (35)(36)(37). This intimate interaction of PSA with membranes is mediated or facilitated by the helical and random-coil conformations of PSA (38). Based on the similar properties of PSA and MARCKS to insert into lipid bilayers, we propose that MARCKS and PSA interact at or within the plasma membrane from opposite sides.…”