PREFERENTIAL SELF-ASSOCIATION OF BASIC FIBROBLAST GROWTH-FACTOR IS STABILIZED BY HEPARIN DURING RECEPTOR DIMERIZATION AND ACTIVATION

Central to signaling by fibroblast growth factors (FGFs) is the oligom eric interaction of the growth factor and its high-affinity cell surfa ce 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 'presen ted' to the FGF receptor for signal transduction. In this study, we sh ow 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, W e 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 polysacchari des only additionally stabilize the FGF-2 self-association. The prefer ential self-association corresponds to FGF-2 translations along two of the unit cell axes of the FGF-2 crystal structures, These two axes re present the two possible heparin binding directions, whereas the recep tor binding sites are oriented along the third axis, Thus, we propose that preferential FGF-2 self-association, further stabilized by hepari n, like ''beads on a string,'' mediates FGF-2-induced receptor dimeriz ation and activation, The observed FGF-2 self-association, modulated b y heparin, not only provides a mechanism of growth factor activation b ut also represents a regulatory mechanism governing FGF-2 biological a ctivity.