Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome

Apert syndrome (AS) is characterized by craniosynostosis (premature fusion of cranial sutures) and severe syndactyly of the hands and feet. Two activa ting mutations, Ser-252 --> Trp and Pro-253 --> Arg, in fibroblast growth f actor receptor 2 (FGFR2) account for nearly all known cases of AS. To eluci date the mechanism by which these substitutions cause AS, we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast g rowth factor 2 (FGF2). These structures demonstrate that both mutations int roduce additional interactions between FGFR2 and FGF2, thereby augmenting F GFR2-FGF2 affinity. Moreover, based on these structures and sequence alignm ent of the FGF family, we propose that the Pro-253 --> Arg mutation will in discriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 --> ,Trp mutation will selectively enhance the affinity of FGFR 2 toward a limited subset of FGFs. These predictions are consistent with pr evious biochemical data describing the effects of AS mutations on FGF bindi ng. Alterations in FGFR2 ligand affinity and specificity may allow inapprop riate autocrine or paracrine activation of FGFR2. Furthermore, the distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among AS patients.