HS (heparan sulphate) proteoglycans bind secreted signalling proteins, including FGFs (fibroblast growth factors) through their HS side chains. Such chains contain a wealth of differentially sulphated saccharide epitopes. Whereas specific HS structures are commonly believed to modulate FGF-binding and activity, selective binding of defined HS epitopes to FGFs has generally not been demonstrated. In the present paper, we have identified a series of sulphated HS octasaccharide epitopes, derived from authentic HS or from biosynthetic libraries that bind with graded affinities to FGF4, FGF7 and FGF8b. These HS species, along with previously identified oligosaccharides that interact with FGF1 and FGF2, constitute the first comprehensive survey of FGF-binding HS epitopes based on carbohydrate sequence analysis. Unexpectedly, our results demonstrate that selective modulation of FGF activity cannot be explained in terms of binding of individual FGFs to specific HS target epitopes. Instead, different FGFs bind to identical HS epitopes with similar relative affinities and low selectivity, such that the strength of these interactions increases with increasing saccharide charge density. We conclude that FGFs show extensive sharing of binding sites in HS. This conclusion challenges the current notion of specificity in HS–FGF interactions, and instead suggests that a set of common HS motifs mediates cellular targeting of different FGFs.
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Research Article|
June 21 2005
Fibroblast growth factors share binding sites in heparan sulphate
Johan KREUGER;
Johan KREUGER
1
*Department of Genetics and Pathology, Uppsala University, The Rudbeck Laboratory, Dag Hammarskjöldsv. 20, SE-75185 Uppsala, Sweden
1To whom correspondence should be addressed (email johan.kreuger@genpat.uu.se).
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Per JEMTH;
Per JEMTH
†Department of Medical Biochemistry and Microbiology, Uppsala University, P.O. Box 582, SE-75123 Uppsala, Sweden
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Emil SANDERS-LINDBERG;
Emil SANDERS-LINDBERG
†Department of Medical Biochemistry and Microbiology, Uppsala University, P.O. Box 582, SE-75123 Uppsala, Sweden
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Liat ELIAHU;
Liat ELIAHU
‡Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
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Dina RON;
Dina RON
‡Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
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Claudio BASILICO;
Claudio BASILICO
§Department of Microbiology, New York University School of Medicine, New York, NY 10016, U.S.A.
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Markku SALMIVIRTA;
Markku SALMIVIRTA
∥Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20520 Turku, Finland
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Ulf LINDAHL
Ulf LINDAHL
†Department of Medical Biochemistry and Microbiology, Uppsala University, P.O. Box 582, SE-75123 Uppsala, Sweden
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Publisher: Portland Press Ltd
Received:
December 22 2004
Revision Received:
February 23 2005
Accepted:
March 16 2005
Accepted Manuscript online:
March 16 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 389 (1): 145–150.
Article history
Received:
December 22 2004
Revision Received:
February 23 2005
Accepted:
March 16 2005
Accepted Manuscript online:
March 16 2005
Citation
Johan KREUGER, Per JEMTH, Emil SANDERS-LINDBERG, Liat ELIAHU, Dina RON, Claudio BASILICO, Markku SALMIVIRTA, Ulf LINDAHL; Fibroblast growth factors share binding sites in heparan sulphate. Biochem J 1 July 2005; 389 (1): 145–150. doi: https://doi.org/10.1042/BJ20042129
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