Crystal structure of fibroblast growth factor 9 reveals regions implicatedin dimerization and autoinhibition

Fibroblast growth factors (FGFs) constitute a large family of heparin-bindi ng growth factors with diverse biological activities. FGF9 was originally d escribed as glia-activating factor and is expressed in the nervous system a s a potent mitogen for glia cells. Unlike most FGFs, FGF9 forms dimers in s olution with a K-d of 680 nr. To elucidate the molecular mechanism of FGF9 dimerization, the crystal structure of FGF9 was determined at 2.2 Angstrom resolution. FGFS adopts a beta -trefoil fold similar to other FGFs. However , unlike other FGFs, the N- and C-terminal regions outside the beta -trefoi l core in FGFS are ordered and involved in the formation of a 2-fold crysta llographic dimer. A significant surface area (>2000 Angstrom (2)) is buried in the dimer interface that occludes a major receptor binding site of FGFS , Thus, we propose an autoinhibitory mechanism for FGFS that is dependent o n sequences outside of the beta -trefoil core. Moreover, a model is present ed providing a molecular basis for the preferential affinity of FGFS toward FGF9.