Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK.
D.E. Shaw Research, New York, New York 10036, USA.
Nat Commun. 2016 Oct 31;7:13307. doi: 10.1038/ncomms13307.
Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced receptor dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of the oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe the structure of EGFR oligomers. We find that at physiological epidermal growth factor (EGF) concentrations, EGFR assembles into oligomers, as indicated by pairwise distances of receptor-bound fluorophore-conjugated EGF ligands. The pairwise ligand distances correspond well with the predictions of our structural model of the oligomers constructed from molecular dynamics simulations. The model suggests that oligomerization is mediated extracellularly by unoccupied ligand-binding sites and that oligomerization organizes kinase-active dimers in ways optimal for auto-phosphorylation in trans between neighbouring dimers. We argue that ligand-induced oligomerization is essential to the regulation of EGFR signalling.
表皮生长因子受体（EGFR）信号通过配体诱导的受体二聚化激活。值得注意的是，配体结合还诱导 EGFR 寡聚化，但寡聚体的结构和功能知之甚少。在这里，我们使用荧光定位成像和光漂白来探测 EGFR 寡聚体的结构。我们发现，在生理表皮生长因子（EGF）浓度下，EGFR 组装成寡聚体，如受体结合的荧光标记 EGF 配体的成对距离所示。成对配体距离与我们从分子动力学模拟构建的寡聚体结构模型的预测非常吻合。该模型表明，寡聚化是由未占据的配体结合位点在细胞外介导的，并且寡聚化以最有利于相邻二聚体之间的自动磷酸化的方式组织激酶活性二聚体。我们认为，配体诱导的寡聚化对于 EGFR 信号转导的调节至关重要。
