Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity
Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity
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DOI：
10.1093/hmg/ddh011
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Mohammadi, M
中科院分区：
文献类型：
--
作者：
Ibrahimi, OA;Zhang, FM;Mohammadi, M
成纤维细胞生长因子受体（FGFR）1（Pro252 Arg）、FGFR 2（Pro253 Arg）和FGFR 3（Pro250 Arg）中相同的脯氨酸->精氨酸功能获得性突变分别导致I型Pfeiffer、Apert和Muenke颅缝早闭综合征。在这里，我们使用表面等离子体共振和X射线晶体学来表征FGFR 1c和FGFR 3c中脯氨酸->精氨酸突变对配体结合的影响。与其各自的野生型受体相比，Pro252 Arg FGFR 1c和Pro250 Arg FGFR 3c均表现出配体结合增强。有趣的是，两种突变受体与FGF 9的结合显著增强，并暗示FGF 9作为突变FGFR在介导颅缝早闭中的潜在病理生理配体。Pro252 Arg FGFR 1c与FGF 2复合物的晶体结构表明，增强的配体结合是由于额外的一组受体-配体氢键，类似于Apert综合征Pro253 Arg FGFR 2c-FGF 2晶体结构中发生的功能获得性相互作用。然而，与Apert综合征Pro253 Arg FGFR 2c突变体不同，Pfeiffer综合征Pro250 Arg FGFR 1c突变体和Muenke综合征Pro250 Arg FGFR 3c突变体均不明显结合FGF 7或FGF 10。这一观察结果为为什么I型Pfeiffer和Muenke综合征中观察到的肢体表型不如Apert综合征中观察到的肢体异常严重提供了可能的解释。因此，尽管FGFR 1 -3中类似的脯氨酸->精氨酸突变通过共同的结构机制起作用以导致功能获得，但FGFR之间一级序列的差异导致对配体结合特异性的不同影响。
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.