Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome - PubMed (original) (raw)

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

O A Ibrahimi et al. Proc Natl Acad Sci U S A. 2001.

Abstract

Apert syndrome (AS) is characterized by craniosynostosis (premature fusion of cranial sutures) and severe syndactyly of the hands and feet. Two activating mutations, Ser-252 --> Trp and Pro-253 --> Arg, in fibroblast growth factor receptor 2 (FGFR2) account for nearly all known cases of AS. To elucidate the mechanism by which these substitutions cause AS, we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2). These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and sequence alignment of the FGF family, we propose that the Pro-253 --> Arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 --> Trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand affinity and specificity may allow inappropriate 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.

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Figures

Figure 1

Figure 1

AS mutations do not affect the relative disposition of D2 and D3 in FGFR2. Cα traces of wild-type (green), mutant Ser252Trp (blue), and Pro253Arg (red) FGFR2s are superimposed. The N and C termini are denoted by the letters NT and CT. This figure was made by using programs MOLSCRIPT (23) and RASTER3D (24). The Cα traces of Ser252Trp and Pro253Arg mutant FGFR2s deviate by only 0.39 Å and 0.31 Å, respectively, from the Cα trace of wild-type FGFR2.

Figure 2

Figure 2

Gain-of-function interactions between the AS mutant FGFR2s and FGF2. (A) Additional contacts between the N terminus of FGF2 and the Ser252Trp mutant FGFR2. (B) Hydrogen bonds between FGF2 and Arg-253 of the Pro253Arg mutant FGFR2. D2 and D3 of FGFR2 are shown in green and cyan, respectively. The short linker that connects D2 and D3 is colored gray. FGF2 is shown in orange. In addition, the FGF2 N-terminal region (Phe21-Pro-Pro-Gly24), which is ordered only in the Ser252Trp mutant FGFR2–FGF2 structure, is colored purple. Oxygen atoms are red, nitrogen atoms blue, and carbon atoms have the same coloring as the molecules to which they belong. Dotted lines represent hydrogen bonds. The hydrogen-bonding distances are indicated. (Right) Views of whole structure in the exact orientation as in the detailed views are shown, and the region of interest is boxed. This figure was created by using the programs MOLSCRIPT and RASTER3D.

Figure 3

Figure 3

Sequence alignment of all 22 known FGFs at regions that are involved in additional contacts with the Ser252Trp (A) or Pro253Arg (B) mutant FGFR2s. The secondary structure assignments were obtained by using the program PROCHECK (32). The location and length of the β-strands are shown on the top of sequence alignments. The numbering of β-strands is according to the published nomenclature (33). A period represents sequence identity to FGF2. FGF2 residues whose side-chain or main-chain atoms are engaged in additional contacts with AS FGFR2s are highlighted with red and green, respectively. The corresponding identical residues in other FGFs also are indicated by using the same coloring scheme. In addition, hydrophobic residues in other FGFs at the position homologous to Phe-21 of FGF2 are highlighted with purple and yellow.

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