Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1
Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1
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DOI：
10.1074/jbc.m111.275891
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发表时间：
2012-01-27
影响因子：
4.8
通讯作者：
Mohammadi, Moosa
中科院分区：
文献类型：
--
作者：
Beenken, Andrew;Eliseenkova, Anna V.;Mohammadi, Moosa
成纤维细胞生长因子受体1 - 3（FGFR 1 - 3）Ig样结构域3（D3）后半部分的组织特异性选择性剪接产生上皮FGFR 1b-FGFR 3b和间充质FGFR 1c-FGFR 3c剪接亚型。该剪接事件建立了选择性过滤器，以限制FGFRb和FGFRc亚型分别与间充质和上皮来源的成纤维细胞生长因子（FGF）的配体结合特异性。FGF1被称为"通用FGFR配体"，因为它克服了这种特异性屏障。为了阐明FGF 1与FGF的"B"和"c"剪接同种型交叉反应性的分子基础，我们在2.1埃分辨率下测定了FGF 1与FGFR B同种型FGFR 2 B复合物的第一晶体结构。FGF1-FGFR2b结构与三种先前公开的FGF1-FGFRc结构的比较揭示，FGF1的N-末端区域与FGFR D3的相互作用中的可塑性是FGF1与FGFR的两种同种型的交叉反应性的主要决定因素。为了支持我们的结构数据，我们证明了FGF2（不结合FGFR2b的配体）的三个N-末端残基（Gly-19、His-25和Phe-26）取代FGF1的相应残基（Phe-16、Asn-22和Tyr-23）使得FGF2三重突变体能够结合并激活FGFR2b。这些发现与我们先前关于FGF 2、FGF 8和FGF 10的受体结合特异性的结构数据一起最终表明，FGF N末端的序列差异是FGF受体结合特异性和混杂性的主要调节因子。
Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1-3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the "universal FGFR ligand" because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the "b" and "c" splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 angstrom resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.