title: Preferential self-association of basic fibroblast growth factor is stabilized by heparin during receptor dimerization and activation.
abstract: Central to signaling by fibroblast growth factors (FGFs) is the oligomeric interaction of the growth factor and its high-affinity cell surface receptor, which is mediated by heparin-like polysaccharides. It has been proposed that the binding of heparin-like polysaccharides to FGF induces a conformational change in FGF, resulting in the formation of FGF dimers or oligomers, and this biologically active form is 'presented' to the FGF receptor for signal transduction. In this study, we show that monomeric basic FGF (FGF-2) preferentially self-associates and forms FGF-2 dimers and higher-order oligomers. As a consequence, FGF-2 monomers are oriented for binding to heparin-like polysaccharides. We also show that heparin-like polysaccharides can readily bind to self-associated FGF-2 without causing a conformational change in FGF-2 or disrupting the FGF-2 self-association, but that the bound polysaccharides only additionally stabilize the FGF-2 self-association. The preferential self-association corresponds to FGF-2 translations along two of the unit cell axes of the FGF-2 crystal structures. These two axes represent the two possible heparin binding directions, whereas the receptor binding sites are oriented along the third axis. Thus, we propose that preferential FGF-2 self-association, further stabilized by heparin, like "beads on a string," mediates FGF-2-induced receptor dimerization and activation. The observed FGF-2 self-association, modulated by heparin, not only provides a mechanism of growth factor activation but also represents a regulatory mechanism governing FGF-2 biological activity.
authors.affiliation: Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Venkataraman
authors.forename: V
authors.initials: V
authors.lastname: Sasisekharan
authors.forename: A B
authors.initials: AB
authors.lastname: Herr
authors.forename: D M
authors.initials: DM
authors.lastname: Ornitz
authors.forename: G
authors.initials: G
authors.lastname: Waksman
authors.forename: C L
authors.initials: CL
authors.lastname: Cooney
authors.forename: R
authors.initials: R
authors.lastname: Langer
authors.forename: R
authors.initials: R
authors.lastname: Sasisekharan
mesh_terms: D001059:Apoproteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002240:Carbohydrate Sequence; D003198:Computer Simulation; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000378:metabolism
chemical_list: D001059:Apoproteins; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D006493:Heparin