Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor
Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor
复制标题
DOI：
10.1128/mcb.00742-10
复制
发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
--
作者：
Lu, Chafen;Mi, Li-Zhi;Springer, Timothy A.
对于表皮生长因子受体 (EGFR) 等具有单次跨膜结构域的受体来说，信号穿过质膜传输以调节信号传导的机制在很大程度上是未知的。表皮生长因子（EGF）二聚化的 EGFR 胞外结构域的晶体结构揭示了延伸的杆状结构域 IV 和与灵活性兼容的小疏水性结构域 IV 界面。晶体结构和二硫键交联表明细胞外域和跨膜域之间的 7 残基连接体是柔性的。跨膜结构域的二硫键交联表明，EGF 仅刺激前两个 α 螺旋转角中度的缔合，而与血型糖蛋白 A 和整联蛋白中超过 5 个 α 螺旋转角的整个膜的缔合相反。此外，亮氨酸和苯丙氨酸的系统诱变表明 EGFR 激酶激活不需要特定的跨膜界面。这些结果表明配体诱导的二聚化和酪氨酸激酶激活之间的联系比之前预想的要松散得多。
The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling are largely unknown for receptors with single-pass transmembrane domains such as the epidermal growth factor receptor (EGFR). A crystal structure of the extracellular domain of EGFR dimerized by epidermal growth factor (EGF) reveals the extended, rod-like domain IV and a small, hydrophobic domain IV interface compatible with flexibility. The crystal structure and disulfide cross-linking suggest that the 7-residue linker between the extracellular and transmembrane domains is flexible. Disulfide cross-linking of the transmembrane domain shows that EGF stimulates only moderate association in the first two alpha-helical turns, in contrast to association throughout the membrane over five alpha-helical turns in glycophorin A and integrin. Furthermore, systematic mutagenesis to leucine and phenylalanine suggests that no specific transmembrane interfaces are required for EGFR kinase activation. These results suggest that linkage between ligand-induced dimerization and tyrosine kinase activation is much looser than was previously envisioned.