Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford, OX11 0QX, UK.
D. E. Shaw Research, New York, NY, 10036, USA.
Nat Commun. 2018 Oct 18;9(1):4325. doi: 10.1038/s41467-018-06632-0.
Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain.
我们目前对表皮生长因子受体 (EGFR) 自身抑制的理解是基于单体和二聚体受体片段的 X 射线结构数据，无法解释突变如何实现配体非依赖性磷酸化。我们使用一系列成像技术和模拟揭示了一种通过该相互作用，各种长度的无配体受体聚合链组装在一起。头对头相互作用的结构阻止了激酶介导的二聚化。这种二聚化是由突变或细胞内处理提供的，将自身抑制的头对头聚合物分裂成由柔性非延伸二聚体组成的茎对茎，该二聚体横跨质膜结构偶联形成活性不对称酪氨酸激酶二聚体，以及与无活性对称激酶二聚体偶联的延伸二聚体。与之前提出的无活性对称激酶二聚体的主要自身抑制功能相反，我们的数据表明，只有失调的物种才具有对称和不对称激酶二聚体的种群，它们在质膜下通过 C 末端结构域的调节处于平衡状态共存。
