Towards a Structure for a TSG-6·Hyaluronan Complex by Modeling and NMR Spectroscopy
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The Link module from human TSG-6, a hyaladherin with roles in ovulation and inflammation, has a hyaluronan (HA)-binding groove containing two adjacent tyrosine residues that are likely to form CH-pi stacking interactions with sequential rings in the sugar. We have used this observation to construct a model of a protein.HA complex, which was then tested against existing experimental information and by acquisition of new NMR data sets of [(13)C, (15)N]HA (8-mer) complexed with unlabeled protein. A major finding of this analysis was that acetamido side chains of two GlcNAc rings fit into hydrophobic pockets on either side of the adjacent tyrosines, providing a selectivity mechanism of HA over other polysaccharides. Furthermore, two basic residues have a separation that matches that of glucuronic acids in the sugar, consistent with the formation of salt bridges; NMR experiments at a range of pH values identified protein groups that titrate due to their proximity to a free carboxylate in HA. Sequence alignment and construction of homology models for all human Link modules in their HA-bound states revealed that many of these features are conserved across the superfamily, thus allowing the prediction of functionally important residues. In the case of cartilage link protein, its two Link modules were docked together (using bound HA as a guide), identifying hydrophobic residues likely to form an intra-Link module interface as well as amino acids that could be involved in supporting intermolecular interactions between link proteins and chondroitin sulfate proteoglycans. Here, we propose a mechanism for ternary complex formation that generates higher order helical structures, as may exist in cartilage aggregates.
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The four Hapln proteins share between 45 and 58 percent amino acid identity, with extremely high homology in their link modules.
“The four Hapln proteins share between 45 and 58% amino acid identity, and the homology in the link modules is extremely high (Bekku et al., 2003;Blundell et al., 2005).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Blundell et al., 2005
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- Authors
- Blundell, C. D., Almond, A., Mahoney, D. J., DeAngelis, P. L., Campbell, I. D., & Day, A. J.
- Affiliations
- University of Oxford (GB)
- University of Oklahoma Health Sciences Center (US)
- Corresponding author
- Day, Anthony J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 280
- Issue
- 18
- Pages
- 18189-18201
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2017606019
- Cited by
- 73
- References
- 69
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 3 · 2012: 3
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- TSG-6, hyaluronic acid, Link module, hyaladherins, protein-polysaccharide complexes, tyrosine side chain, hydrophobic pocket, salt bridges, glucuronic acid, pH titration, homology modeling, chondroitin sulfate proteoglycans, ternary complex formation, helical conformation
- MeSH terms
- Acetylglucosamine, Amino Acid Sequence, Animals, Multigene Family, Humans, Hyaluronic Acid, Male, Models, Molecular, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Protein Binding, Protein Conformation, Sheep, Cell Adhesion Molecules, Mutagenesis, Site-Directed, Conserved Sequence, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, Amino Acid Motifs
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