Ligand-induced structural transitions in ErbB receptor extracellular domains
Ligand-induced structural transitions in ErbB receptor extracellular domains
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DOI：
10.1016/j.str.2007.06.013
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发表时间：
2007-08-01
期刊：
影响因子：
5.7
通讯作者：
Lemmon, Mark A.
中科院分区：
文献类型：
--
作者：
Dawson, Jessica P.;Bu, Zimei;Lemmon, Mark A.
晶体学研究表明，表皮生长因子（EGF）受体的激活涉及主要的结构域重排。没有结合配体，受体的细胞外区域（sEGFR）采用“系留”结构，其二聚化位点被明显的自抑制分子内相互作用所封闭。配体结合使受体变得“延伸”，打破系链并暴露二聚化位点。利用小角度x射线散射（SAXS），我们证实了溶液中也存在系链和延伸构象，并描述了完整sEGFR二聚体的低分辨率分子包膜。我们还使用SAXS直接监测ErbB3的单体细胞外区域和二聚体缺陷EGFR突变体从栓系结构到扩展结构的转变。最后，我们表明，突变sEGFR中的每个分子内系绳相互作用不会大大改变其构象。这些发现解释了为什么tether突变体不能激活EGF受体，并为ErbB受体构象的调节提供了新的见解。
Crystallographic studies showed that epidermal growth factor (EGF) receptor activation involves major domain rearrangements. Without bound ligand, the extracellular region of the receptor (sEGFR) adopts a "tethered" configuration with its dimerization site occluded by apparently autoinhibitory intramolecular interactions. Ligand binding causes the receptor to become "extended," breaking the tether and exposing the dimerization site. Using small-angle X-ray scattering (SAXS), we confirm that the tethered and extended conformations are also adopted in solution, and we describe low-resolution molecular envelopes for an intact sEGFR dimer. We also use SAXS to monitor directly the transition from a tethered to extended configuration in the monomeric extracellular regions of ErbB3 and a dimerization defective EGFR mutant. Finally, we show that mutating every intramolecular tether interaction in sEGFR does not greatly alter its conformation. These findings explain why tether mutants fail to activate EGF receptor and provide new insight into regulation of ErbB receptor conformation.