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Crystal Structure of Fibroblast Growth Factor 9 Reveals Regions Implicated in Dimerization and Autoinhibition

2001; Elsevier BV; Volume: 276; Issue: 6 Linguagem: Inglês

10.1074/jbc.m006502200

1083-351X

A.N. Plotnikov, Anna V. Eliseenkova, Omar A. Ibrahimi, Zachary Shriver, Ram Sasisekharan, Mark A. Lemmon, Moosa Mohammadi,

Metabolism, Diabetes, and Cancer

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 Å resolution. FGF9 adopts a β-trefoil fold similar to other FGFs. However, unlike other FGFs, the N- and C-terminal regions outside the β-trefoil core in FGF9 are ordered and involved in the formation of a 2-fold crystallographic dimer. A significant surface area (>2000 Å 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 β-trefoil core. Moreover, a model is presented providing a molecular basis for the preferential affinity of FGF9 toward FGFR3.