Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.
Identical proline-->arginine gain-of-function mutations in fibroblast growth factor receptor (FGFR) 1 (Pro252Arg), FGFR2 (Pro253Arg) and FGFR3 (Pro250Arg), result in type I Pfeiffer, Apert and Muenke craniosynostosis syndromes, respectively. Here, we characterize the effects of proline-->arginine mutations in FGFR1c and FGFR3c on ligand binding using surface plasmon resonance and X-ray crystallography. Both Pro252Arg FGFR1c and Pro250Arg FGFR3c exhibit an enhancement in ligand binding in comparison to their respective wild-type receptors. Interestingly, binding of both mutant receptors to FGF9 was notably enhanced and implicates FGF9 as a potential pathophysiological ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure, of Pro252Arg FGFR1c in complex with FGF2, demonstrates that the enhanced ligand binding is due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the Apert syndrome Pro253Arg FGFR2c-FGF2 crystal structure. However, unlike the Apert syndrome Pro253Arg FGFR2c mutant, neither the Pfeiffer syndrome Pro250Arg FGFR1c mutant nor the Muenke syndrome Pro250Arg FGFR3c mutant bound appreciably to FGF7 or FGF10. This observation provides a potential explanation for why the limb phenotypes, observed in type I Pfeiffer and Muenke syndromes, are less severe than the limb abnormalities observed in Apert syndrome. Hence, although analogous proline-->arginine mutations in FGFR1-3 act through a common structural mechanism to result in gain-of-function, differences in the primary sequence among FGFRs result in varying effects on ligand binding specificity.
Ibrahimi
Omar A
OA
Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Zhang
Fuming
F
Eliseenkova
Anna V
AV
Linhardt
Robert J
RJ
Mohammadi
Moosa
M
D000596:Amino Acids / Q000378:metabolism; D002845:Chromatography; D003398:Craniosynostoses / Q000235:genetics*; D018360:Crystallography, X-Ray; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D017354:Point Mutation / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D020836:Protein Structure, Quaternary; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism*; D020349:Surface Plasmon Resonance
D000596:Amino Acids; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D008024:Ligands; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors