Springer B A, Pantoliano M W, Barbera F A, Gunyuzlu P L, Thompson L D, Herblin W F, Rosenfeld S A, Book G W
Department of Crystallography, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0228.
J Biol Chem. 1994 Oct 28;269(43):26879-84.
Members of the fibroblast growth factor (FGF) family promote angiogenesis and wound repair, modulate early developmental events and survival of neurons, and have been associated with the pathogenesis of various diseases. FGFs interact with specific FGF receptors (FGFRs) and heparan sulfate proteoglycans on cell surfaces to mediate mitogenesis. Using protein structure-based site-directed mutagenesis of basic FGF (bFGF), we have identified two FGFR binding sites on bFGF which act in concert to initiate signal transduction. Both FGFR binding surfaces are distinct from the heparan sulfate proteoglycan binding domain. The primary, higher affinity, binding interaction comprises a cluster of solvent exposed hydrophobic amino acids (Tyr-24, Tyr-103, Leu-140, and Met-142), and two polar residues (Arg-44 and Asn-101). The hydrophobic contacts dominate the primary binding interaction and provide approximately 75% of the binding affinity. The secondary FGFR binding site on bFGF has an approximately 250-fold lower affinity and is composed of amino acids Lys-110, Tyr-111, and Trp-114 in a surface-exposed type I beta-turn (formerly known as the putative receptor binding loop). Binding of FGFR to both bFGF surfaces in a stoichiometry of 2FGFR:1bFGF is required for growth factor mediated cell proliferation. This represents a mechanism for the fibroblast growth factor/receptor family in which FGF facilitates FGFR dimerization and subsequent signal transduction events as a monomeric ligand.
成纤维细胞生长因子（FGF）家族成员可促进血管生成和伤口修复，调节早期发育事件及神经元存活，并与多种疾病的发病机制相关。FGF与细胞表面特定的FGF受体（FGFR）和硫酸乙酰肝素蛋白聚糖相互作用，介导有丝分裂。通过对碱性FGF（bFGF）进行基于蛋白质结构的定点诱变，我们在bFGF上鉴定出两个FGFR结合位点，它们协同作用以启动信号转导。两个FGFR结合表面均与硫酸乙酰肝素蛋白聚糖结合域不同。主要的、亲和力较高的结合相互作用包括一组暴露于溶剂中的疏水氨基酸（Tyr-24、Tyr-103、Leu-140和Met-142）以及两个极性残基（Arg-44和Asn-101）。疏水接触主导主要的结合相互作用，并提供约75%的结合亲和力。bFGF上的次要FGFR结合位点亲和力约低250倍，由处于表面暴露的I型β-转角（以前称为假定的受体结合环）中的氨基酸Lys-110、Tyr-111和Trp-114组成。FGFR以2FGFR:1bFGF的化学计量比与bFGF的两个表面结合是生长因子介导的细胞增殖所必需的。这代表了成纤维细胞生长因子/受体家族的一种机制，其中FGF作为单体配体促进FGFR二聚化及随后的信号转导事件。
