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. Author manuscript; available in PMC: 2013 Jan 11.
Published in final edited form as: Structure. 2012 Jan 11;20(1):77–88. doi: 10.1016/j.str.2011.10.022

Figure 6. The AB Subregion of the AB/Linker Region Is Highly Conserved among FGFR Orthologs and Acts at Three Levels to Autoinhibit FGFR Signaling.

Figure 6

(A) Sequence alignment of the AB/linker region from the indicated FGFR3 orthologs and from fruit fly FGFR1 and FGFR2 indicates that the AB subregion is conserved throughout evolution.

(B) Sequence alignment of the AB/linker region from human FGFR1-FGFR4. The residues highlighted by a red box represent the AB subregion. Periods indicate spaces introduced into the sequences to improve the alignments.

(C) FGFR exists in a dynamic equilibrium between open and closed conformations. In the closed state, the cis interaction between the AB subregion and the HBS autoinhibits binding of both HS and ligand to the FGFR, thereby suppressing ligand- and HS-mediated receptor dimerization and subsequent FGFR activation. The cis interaction may also sterically inhibit D2-mediated receptor-receptor interaction because of close proximity of the HS and receptor-receptor binding sites on D2. FGF and HS bind to the open state forming the 2:2:2 FGFR:FGF:HS signaling unit. In the open state, the HS binds to the HBS on D2, posing risk of HS-mediated ligand-independent receptor dimerization.