Heparin-induced Self-association of Fibroblast Growth Factor-2
EVIDENCE FOR TWO OLIGOMERIZATION PROCESSES*
- From the Departments of ‡Biochemistry and Molecular Biophysics and §Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ¶Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Abstract
Fibroblast growth factor-2 (FGF-2), a potent angiogenic factor, requires heparin for dimerization and activation of the FGF receptor tyrosine kinase. The binding of multiple fibroblast growth factors by heparin may be necessary for dimerization of the FGF receptor. Analytical ultracentrifugation of FGF-2 in the presence of heparin-derived saccharides shows that both an active heparin octasaccharide and an inactive heparin-like disaccharide induce fibroblast growth factor-2 self-association. Analysis of the data indicates that the heparin octasaccharide induces a monomer-dimer-tetramer assembly of FGF-2 while the disaccharide induces a monomer-dimer equilibrium. Evidence is presented indicating that the dimer conformation induced by the heparin octasaccharide is a side by side dimer with the FGF-2 molecules cis to the heparin, while the disaccharide-induced dimer is a head to head dimer in which FGF-2 molecules are trans to the ligand. These results, combined with previous studies, support the model that formation of a specific side by side heparin-induced FGF-2 dimer is required for activation of the FGF receptor.
Footnotes
-
↵* This work was supported by National Institutes of Health Biophysics Training Grant 5 T32 GM08492–04 (to A. B. H.), National Institutes of Health Grant CA60673 (to D. M. O.), National Institutes of Health Grant DK51207 (to R. S.), and funds from the Department of Biochemistry and Molecular Biophysics of Washington University School of Medicine (to G. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵‖ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-4562; Fax: 314-362-7183.
-
↵1 The abbreviations used are: FGF-2, fibroblast growth factor-2; HS, heparin or heparan sulfate; HSPG, heparan sulfate proteoglycan; FGFR, fibroblast growth factor receptor; FGF-1, fibroblast growth factor-1; HS-8, sulfated heparin octasaccharide; SOS, sucrose octasulfate; β-ME, β-mercaptoethanol; EGF, epidermal growth factor.
-
- Received October 18, 1996.
- Revision received March 27, 1997.
