Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity

• DOI: 10.1073/pnas.0307287101
• Publication Date: 2004-01-27T18:23:16Z
• Authors: Shaun K. Olsen; Omar A. Ibrahimi; Angela Raucci; Fuming Zhang; Anna V. Eliseenkova; Avner Yayon; Claudio Basilico; Robert J. Linhardt; Joseph Schlessinger; Moosa Mohammadi
• Keywords: FGF1

The prototypical fibroblast growth factor receptor (FGFR) extracellular domain consists of three Ig domains (D1–D3) which the two membrane-proximal D2 and D3 interconnecting D2–D3 linker bear determinants ligand binding specificity. In contrast, D1 D1–D2 are thought to play autoinhibitory roles in FGFR regulation. Here, we report crystal structure three-Ig form FGFR3c complex with FGF1, an FGF that binds promiscuously each seven principal FGFRs. this structure, completely disordered, demonstrating these regions dispensable for binding. Real-time experiments using surface plasmon resonance show relative two-Ig form, exhibits lower affinity both FGF1 heparin. Importantly, demonstrate autoinhibition is mediated by intramolecular interactions minimal heparin-binding region. As FGF1–FGFR2c but not FGF1–FGFR1c alternatively spliced βC′–βE loop ordered interacts FGF1–FGFR3c structure. However, contrast β-trefoil core region extensively N-terminal underscoring importance N terminus conferring receptor-binding promiscuity. comparison FGF1–FGFR structures shows flexibility a major determinant ligand-binding specificity