Structural specificity of heparin binding in the fibroblast growth factor family of proteins.
Heparin and heparan sulfate glycosaminoglycans (HSGAGs) mediate a wide variety of complex biological processes by specifically binding proteins and modulating their biological activity. One of the best studied model systems for protein-HSGAG interactions is the fibroblast growth factor (FGF) family of molecules, and recent observations have demonstrated that the specificity of a given FGF ligand binding to its cognate receptor (FGFR) is mediated by distinct tissue-specific HSGAG sequences. Although it has been known that sulfate and carboxylate groups in the HSGAG chain play a key role by interacting with basic residues on the proteins, there is little understanding of how these ionic interactions provide the necessary specificity for protein binding. In this study, using all of the available crystal structures of different FGFs and FGF-HSGAG complexes, we show that in addition to the ionic interactions, optimal van der Waals contact between the HSGAG oligosaccharide and the protein is also very important in influencing the specificity of FGF-HSGAG interactions. Although the overall helical structure is maintained in the FGF-bound HSGAG compared with unbound HSGAG, we observe distinct changes in the backbone torsion angles of the oligosaccharide chain induced upon protein binding. These changes result in local deviations in the helical axis that provide optimal ionic and van der Waals contact with the protein. A specific conformation and topological arrangement of the HSGAG-binding loops of FGF, on the other hand, impose structural constraints that induce the local deviations in the HSGAG structure, thereby enabling maximum contact between HSGAG and the protein.
Raman
Rahul
R
Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Venkataraman
Ganesh
G
Ernst
Steffen
S
Sasisekharan
V
V
Sasisekharan
Ram
R
D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D018360:Crystallography, X-Ray; D019992:Databases as Topic; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000737:chemistry*; D006801:Humans; D007067:Iduronic Acid / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
C496453:FGF7 protein, human; D008024:Ligands; D009844:Oligosaccharides; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D051523:Fibroblast Growth Factor 7; D007067:Iduronic Acid; D005346:Fibroblast Growth Factors; D006493:Heparin