Fibroblast growth factors share binding sites in heparan sulphate.
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.
Kreuger
Johan
J
Department of Genetics and Pathology, Uppsala University, The Rudbeck Laboratory, Dag Hammarskjöldsv. 20, SE-75185 Uppsala, Sweden. johan.kreuger@genpat.uu.se
Jemth
Per
P
Sanders-Lindberg
Emil
E
Eliahu
Liat
L
Ron
Dina
D
Basilico
Claudio
C
Salmivirta
Markku
M
Lindahl
Ulf
U
D001665:Binding Sites; D000939:Epitopes; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding
D000939:Epitopes; D016220:Fibroblast Growth Factor 1; D051519:Fibroblast Growth Factor 4; D051523:Fibroblast Growth Factor 7; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate