Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors
Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors
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DOI：
10.1073/pnas.0436500100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
Mohammadi, M
中科院分区：
文献类型：
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作者：
Yeh, BK;Igarashi, M;Mohammadi, M
成纤维细胞生长因子(FGFs)与其受体(FGFRs)之间的结合特异性对哺乳动物的发育至关重要，主要受FGFRs Ig样结构域3(D3)的后半部分编码的两个选择性剪接外显子IIIb(“b”)和IIIc(“c”)调控。FGF7和FGF10仅激活B型FGFR2(FGFR2b)。在这里，我们报道了FGFR2b与FGF10结合的配体结合部分的晶体结构。FGF10中分歧区与D3中两个b-特异性环之间的独特接触揭示了替代剪接提供FGF10-FGFR2b特异性的结构基础。FGF10的基于结构的突变证实了观察到的接触对FGF10生物活性的重要性。有趣的是，FGF10结合诱导受体Ig结构域2(D2)发生以前未观察到的旋转，从而引入与FGF10的特定接触。因此，FGFR2b的D2和D3都有助于FGF10和FGFR2b之间的特殊特异性。我们认为，配体诱导的FGFRs构象变化也可能在决定其他成纤维细胞生长因子-FGFR复合体的特异性方面发挥重要作用。
Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb ("b") and IIIc ("c"), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes.