A refined model for the TSG-6 link module in complex with hyaluronan: use of defined oligosaccharides to probe structure and function.

Higman, V; Briggs, D; Mahoney, D; Blundell, C; Sattelle, B; Dyer, D; Green, D; DeAngelis, P; Almond, A; Milner, C; Day, A

Women's Health Collection

Journal article

A refined model for the TSG-6 link module in complex with hyaluronan: use of defined oligosaccharides to probe structure and function.

Abstract:: Tumor necrosis factor-stimulated gene-6 (TSG-6) is an inflammation-associated hyaluronan (HA)-binding protein that contributes to remodeling of HA-rich extracellular matrices during inflammatory processes and ovulation. The HA-binding domain of TSG-6 consists solely of a Link module, making it a prototypical member of the superfamily of proteins that interacts with this high molecular weight polysaccharide composed of repeating disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine (GlcNAc). Previously we modeled a complex of the TSG-6 Link module in association with an HA octasaccharide based on the structure of the domain in its HA-bound conformation. Here we have generated a refined model for a HA/Link module complex using novel restraints identified from NMR spectroscopy of the protein in the presence of 10 distinct HA oligosaccharides (from 4- to 8-mers); the model was then tested using unique sugar reagents, i.e. chondroitin/HA hybrid oligomers and an octasaccharide in which a single sugar ring was (13)C-labeled. The HA chain was found to make more extensive contacts with the TSG-6 surface than thought previously, such that a D-glucuronic acid ring makes stacking and ionic interactions with a histidine and lysine, respectively. Importantly, this causes the HA to bend around two faces of the Link module (resembling the way that HA binds to CD44), potentially providing a mechanism for how TSG-6 can reorganize HA during inflammation. However, the HA-binding site defined here may not play a role in TSG-6-mediated transfer of heavy chains from inter-α-inhibitor onto HA, a process known to be essential for ovulation.

Publication status:: Published

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APA Style

Higman, V., Briggs, D., Mahoney, D., Blundell, C., Sattelle, B., Dyer, D., Green, D., DeAngelis, P., Almond, A., Milner, C., & Day, A. (2014). A refined model for the TSG-6 link module in complex with hyaluronan: use of defined oligosaccharides to probe structure and function. Journal of Biological Chemistry, 289(9), 5619–5634.

MLA Style

Higman, V, et al. “A Refined Model for the TSG-6 Link Module in Complex with Hyaluronan: Use of Defined Oligosaccharides to Probe Structure and Function.” Journal of Biological Chemistry, vol. 289, no. 9, 2014, pp. 5619–34.

Chicago Style

Higman, V, D Briggs, D Mahoney, et al. 2014. “A Refined Model for the TSG-6 Link Module in Complex with Hyaluronan: Use of Defined Oligosaccharides to Probe Structure and Function.” Journal of Biological Chemistry 289 (9): 5619–34.
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