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Chemical modification of hyaluronan oligosaccharides differentially modulates hyaluronan-hyaladherin interactions.
Dodd, Rebecca J; Blundell, Charles D; Sattelle, Benedict M; Enghild, Jan J; Milner, Caroline M; Day, Anthony J.
Afiliación
  • Dodd RJ; Wellcome Centre for Cell Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, M13 9PT, United Kingdom.
  • Blundell CD; C4X Discovery, 53 Portland Street, M1 3LD, Manchester, United Kingdom.
  • Sattelle BM; C4X Discovery, 53 Portland Street, M1 3LD, Manchester, United Kingdom.
  • Enghild JJ; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • Milner CM; Wellcome Centre for Cell Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, M13 9PT, United Kingdom; Division of Cell Ma
  • Day AJ; Wellcome Centre for Cell Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, M13 9PT, United Kingdom; Division of Cell Ma
J Biol Chem ; : 107668, 2024 Aug 09.
Article en En | MEDLINE | ID: mdl-39128716
ABSTRACT
The glycosaminoglycan hyaluronan (HA) is a ubiquitous, non-sulfated polysaccharide with diverse biological roles mediated through its interactions with HA-binding proteins (HABPs). Most HABPs belong to the Link module superfamily, including the major HA receptor, CD44, and secreted protein TSG-6, which catalyzes the covalent transfer of Heavy Chains (HC) from inter-α-inhibitor (IαI) onto HA. The structures of the HA-binding domains (HABD) of CD44 (HABD_CD44) and TSG-6 (Link_TSG6) have been determined and their interactions with HA extensively characterized. The mechanisms of binding are different, with Link_TSG6 interacting with HA primarily via ionic and CH-π interactions, whereas HABD_CD44 binds solely via hydrogen bonds and van der Waals forces. Here we exploit these differences to generate HA oligosaccharides, chemically modified at their reducing ends, that bind specifically and differentially to these target HABPs. Hexasaccharides (HA6AN) modified with 2- or 3-aminobenzoic acid or 2-amino-4-methoxybenzoic acid (HA6-2AA, HA6-3AA, HA6-2A4MBA, respectively) had increased affinities for Link_TSG6 compared to unmodified HA6AN. These modifications did not increase the affinity for CD44_HABD. A model of HA6-2AA (derived from the solution dynamic 3D structure of HA4-2AA) was docked into the Link_TSG6 structure, providing evidence that the 2AA-carboxyl forms a salt bridge with Arginine-81. These modeling results informed a 2nd series of chemical modifications for HA oligosaccharides, which again showed differential binding to the two proteins. Several modifications to HA4 and HA6 were found to convert the oligosaccharide into substrates for HC-transfer, whereas unmodified HA4 and HA6 are not. This study has generated valuable research tools to further understand HA biology.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos