title: Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition.
abstract: Fibroblast growth factors (FGFs) constitute a large family of heparin-binding growth factors with diverse biological activities. FGF9 was originally described as glia-activating factor and is expressed in the nervous system as a potent mitogen for glia cells. Unlike most FGFs, FGF9 forms dimers in solution with a K(d) of 680 nm. To elucidate the molecular mechanism of FGF9 dimerization, the crystal structure of FGF9 was determined at 2.2 A resolution. FGF9 adopts a beta-trefoil fold similar to other FGFs. However, unlike other FGFs, the N- and C-terminal regions outside the beta-trefoil core in FGF9 are ordered and involved in the formation of a 2-fold crystallographic dimer. A significant surface area (>2000 A(2)) is buried in the dimer interface that occludes a major receptor binding site of FGF9. Thus, we propose an autoinhibitory mechanism for FGF9 that is dependent on sequences outside of the beta-trefoil core. Moreover, a model is presented providing a molecular basis for the preferential affinity of FGF9 toward FGFR3.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: A V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: O A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: Z
authors.initials: Z
authors.lastname: Shriver
authors.forename: R
authors.initials: R
authors.lastname: Sasisekharan
authors.forename: M A
authors.initials: MA
authors.lastname: Lemmon
authors.forename: M
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D051525:Fibroblast Growth Factor 9; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors