4.7 Article

Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization

Journal

STRUCTURE
Volume 25, Issue 9, Pages 1325-+

Publisher

CELL PRESS
DOI: 10.1016/j.str.2017.06.016

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Funding

  1. National Institute of Dental and Craniofacial Research [DE13686]

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The epithelial fibroblast growth factor 9 (FGF9) subfamily specifically binds and activates the mesenchymal c'' splice isoform of FGF receptors 1-3 (FGFR1-3) to regulate organogenesis and tissue homeostasis. The unique N and C termini of FGF9 subfamily ligands mediate a reversible homodimerization that occludes major receptor binding sites within the ligand core region. Here we provide compelling X-ray crystallographic, biophysical, and biochemical data showing that homodimerization controls receptor binding specificity of the FGF9 subfamily by keeping the concentration of active FGF9 monomers at a level, which is sufficient for a normal FGFR c'' isoform binding/signaling, but is insufficient for an illegitimate FGFR b'' isoform binding/signaling. We show that deletion of the N terminus or alanine substitutions in the C terminus of FGF9 skews the delicate ligand equilibrium toward active FGF9 monomers causing off-target binding and activation of FGFR b isoforms. Our study is the first to implicate ligand homodimerization in the regulation of ligand-receptor specificity.

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