Structure of a heparin-linked biologically active dimer of fibroblast growth factor.
The fibroblast growth factors (FGFs) form a large family of structurally related, multifunctional proteins that regulate various biological responses. They mediate cellular functions by binding to transmembrane FGF receptors, which are protein tyrosine kinases. FGF receptors are activated by oligomerization, and both this activation and FGF-stimulated biological responses require heparin-like molecules as well as FGF. Heparins are linear anionic polysaccharide chains; they are typically heterogeneously sulphated on alternating L-iduronic and D-glucosamino sugars, and are nearly ubiquitous in animal tissues as heparan sulphate proteoglycans on cell surfaces and in the extracellular matrix. Although several crystal structures have been described for FGF molecules in complexes with heparin-like sugars, the nature of a biologically active complex has been unknown until now. Here we describe the X-ray crystal structure, at 2.9 A resolution, of a biologically active dimer of human acidic FGF in a complex with a fully sulphated, homogeneous heparin decassacharide. The dimerization of heparin-linked acidic FGF observed here is an elegant mechanism for the modulation of signalling through combinatorial homodimerization and heterodimerization of the 12 known members of the FGF family.
DiGabriele
A D
AD
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Lax
I
I
Chen
D I
DI
Svahn
C M
CM
Jaye
M
M
Schlessinger
J
J
Hendrickson
W A
WA
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D019281:Dimerization; D004926:Escherichia coli; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D016716:PC12 Cells; D011487:Protein Conformation; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D009844:Oligosaccharides; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D016220:Fibroblast Growth Factor 1; D006493:Heparin