Sequence analysis of heparan sulfate epitopes with graded affinities for fibroblast growth factors 1 and 2.
Proteins that belong to the fibroblast growth factor (FGF) family regulate proliferation, migration, and differentiation of many cell types. Several FGFs, including the prototype factors FGF-1 and FGF-2, depend on interactions with heparan sulfate (HS) proteoglycans for activity. We have assessed tissue-derived HS fragments for binding to FGF-1 and FGF-2 to identify the authentic saccharide motifs required for interactions. Sequence information on a range of N-sulfated HS octasaccharides spanning from low to high affinity for FGF-1 was obtained. All octasaccharides with high affinity for FGF-1 (> or =0.5 m NaCl required for elution) contained an internal IdoUA(2-OSO(3))-GlcNSO(3)(6-OSO(3))-IdoUA(2-OSO(3))-trisaccharide motif. Octasaccharides with a higher overall degree of sulfation but lacking the specific trisaccharide motif showed lower affinity for FGF-1. FGF-2 was shown to bind to a mono-O-sulfated HS 6-mer carrying a single internal IdoUA(2-OSO(3))-unit. However, a di-O-sulfated -IdoUA(2-OSO(3))-GlcNSO(3)-IdoUA(2-OSO(3))-trisaccharide sequence within a HS 8-mer gave stronger binding. These findings show that not only the number but also the positions of individual sulfate groups determine affinity of HS for FGFs. Our findings support the notion that FGF-dependent processes can be modulated in vivo by regulated expression of distinct HS sequences.
Kreuger
J
J
Department of Medical Biochemistry and Microbiology, Uppsala University, S-75123 Uppsala, Sweden.
Salmivirta
M
M
Sturiale
L
L
Giménez-Gallego
G
G
Lindahl
U
U
D002240:Carbohydrate Sequence; D000939:Epitopes / Q000737:chemistry*; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry / Q000276:immunology*
D000939:Epitopes; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate