Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4
Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4
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DOI：
10.1074/jbc.m011226200
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发表时间：
2001-05-18
影响因子：
4.8
通讯作者：
Salmivirta, M
中科院分区：
文献类型：
--
作者：
Loo, BM;Kreuger, J;Salmivirta, M
成纤维细胞生长因子（FGF）是影响许多细胞类型的生长、分化和迁移的肝素结合多肽。FGF通过结合并激活细胞表面FGF受体（FGFR）与细胞内酪氨酸激酶结构域来进行信号传导。信号传导涉及配体诱导的受体二聚化和自磷酸化，随后是信号的下游转移。硫酸化糖胺聚糖肝素和硫酸乙酰肝素结合FGF和FGFR，并通过介导生长因子和受体组分之间的复合物形成来增强FGF信号传导。虽然参与FGF结合的肝素/硫酸乙酰肝素结构已被详细研究，但关于介导与FGFR结合的糖结构的信息很少。我们已经对具有FGFR 4亲和力的肝素/硫酸乙酰肝素寡糖进行了结构表征。肝素寡糖与FGFR 4的结合随着片段长度的增加而增加，最小结合域包含在8个单糖单元内。FGFR 4结合糖结构域含有2-O-硫酸化艾杜糖醛酸和6-O-硫酸化N-磺基葡萄糖胺残基，如选择性肝素实验、组成二糖分析和硫酸乙酰肝素寡糖的新型外切酶序列分析所示。结构上不同的硫酸乙酰肝素八糖与FGFR 4的结合不同。序列分析表明，相互作用的亲和力依赖于6-O-硫酸基团的数量，但不依赖于它们的精确位置。
Fibroblast growth factors (FGFs) are heparin-binding polypeptides that affect the growth, differentiation, and migration of many cell types. FGFs signal by binding and activating cell surface FGF receptors (FGFRs) with intracellular tyrosine kinase domains. The signaling involves ligand-induced receptor dimerization and autophosphorylation, followed by downstream transfer of the signal. The sulfated glycosaminoglycans heparin and heparan sulfate bind both FGFs and FGFRs and enhance FGF signaling by mediating complex formation between the growth factor and receptor components. Whereas the heparin/heparan sulfate structures involved in FGF binding have been studied in some detail, little information has been available on saccharide structures mediating binding to FGFRs. We have performed structural characterization of heparin/heparan sulfate oligosaccharides with affinity toward FGFR4. The binding of heparin oligosaccharides to FGFR4 increased with increasing fragment length, the minimal binding domains being contained within eight monosaccharide units. The FGFR4-binding saccharide domains contained both 2-O-sulfated iduronic acid and 6-O-sulfated N-sulfoglucosamine residues, as shown by experiments with selectively desulfated heparin, compositional disaccharide analysis, and a novel exoenzyme-based sequence analysis of heparan sulfate oligosaccharides. Structurally distinct heparan sulfate octasaccharides differed in binding to FGFR4. Sequence analysis suggested that the affinity of the interaction depended on the number of 6-O-sulfate groups but not on their precise location.