Structural basis for FGF receptor dimerization and activation.

By A. Plotnikov, Joseph Schlessinger, S. Hubbard, M. Mohammadi. 1999

The crystal structure of FGF2 bound to a naturally occurring variant of FGF receptor 1 (FGFR1) consisting of immunoglobulin-like domains 2 (D2) and 3 (D3) has been determined at 2.8 A resolution. Two FGF2:FGFR1 complexes form a 2-fold symmetric dimer. Within each complex, FGF2 interacts extensively with D2 and D3 as well as with the linker between the two domains. The dimer is stabilized by interactions between FGF2 and D2 of the adjoining complex and by a direct interaction between D2 of each receptor. A positively charged canyon formed by a cluster of exposed basic residues likely represents the heparin-binding site. A general model for FGF- and heparin-induced FGFR dimerization is inferred from the crystal structure, unifying a wealth of biochemical data.

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8. O. Ibrahimi

Citations in the corpus

• Structural basis for fibroblast growth factor receptor activation. (2005, background): “the FGF2–FGFR1c complex (PDB ID: 1CVS) [127].”
• Fibroblast growth factors, their receptors and signaling. (2000, background): “In each of the FGF-FGFR pairs, IgII and IgIII both wrap around a single FGF molecule: IgII binding at Springer’s high affinity binding site (see above) and IgIII binding at the low affinity site (Venkataramanet al. 1999) or with other amino acids (Plotnikov et al. 1999, Stauberet al. 2000).”
• Basement membranes: cell scaffoldings and signaling platforms. (2011, unknown): “Such heparin-binding factors include fibroblast growth factors (FGF, especially FGF-2), transforming growth factor-b (TGFb1,2), bone morphogenic proteins (BMPs-2,4,7), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factors (VEGF), heparin-binding epidermal growth factor (HB-EG”
• Amino‐Acid Properties and Consequences of Substitutions (2003, background): “2), interact over a large surface, with virtually any amino acid being important in mediating the interaction (Plotnikov et al., 1999).”
• Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. (2000, background): “Each of the FGFRs binds to a unique subset of FGFs accounting for the tight regulation and diversity in response to FGF stimulation (Ornitz Joseph Schlessinger,*‖ Alexander N. Plotnikov,*‖ Omar A. Ibrahimi,* Anna V. Eliseenkova,* Brian K. Yeh,* Avner Yayon,† Robert J. Linhardt,‡ and Moosa Mohammadi*”
• Structural systems biology: modelling protein interactions (2006, background): “Crystal structures are available for the interaction of FGF1 and FGF2 with two of the three extracellular domains of the receptors FGFR1 and FGFR2a, respectively (see, for example, Ref”
• Mechanisms underlying differential responses to FGF signaling. (2005, background): “All other FGFs share considerable homology within a conserved ‘‘core’’ sequence of about 100 amino acids and, although exhibiting somewhat different but overlapping receptor binding specificity, are all likely to bind FGFR by establishing interaction with the D2–D3 domains of FGFR and with heparin [”
• Protein-protein interactions define specificity in signal transduction. (2000, background): “The binding of a hormone to such receptors induces either receptor oligomerization (Heldin et al. 1995; Plotnikov et al. 1999) or the spatial reorientation of preclustered chains, as shown for the erythropoietin receptor (Remy et al. 1999).”
• Role of tissue stroma in cancer cell invasion (2003, background): “Crystallographic studies revealed that the histidine and valine side chains of the HAV sequence in FGFR1 are involved in intradomain contacts and are, therefore, not available for interaction with other molecules [178].”