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首页> 外文期刊>Molecular and Cellular Biology >Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor
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Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor

机译：C末端尾巴在表皮生长因子受体调控中的作用分析

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The ～230-residue C-terminal tail of the epidermal growth factor receptor (EGFR) is phosphorylated upon activation. We examined whether this phosphorylation is affected by deletions within the tail and whether the two tails in the asymmetric active EGFR dimer are phosphorylated differently. We monitored autophosphorylation in cells using flow cytometry and found that the first ～80 residues of the tail are inhibitory, as demonstrated previously. The entire ～80-residue span is important for autoinhibition and needs to be released from both kinases that form the dimer. These results are interpreted in terms of crystal structures of the inactive kinase domain, including two new ones presented here. Deletions in the remaining portion of the tail do not affect autophosphorylation, except for a six-residue segment spanning Tyr 1086 that is critical for activation loop phosphorylation. Phosphorylation of the two tails in the dimer is asymmetric, with the activator tail being phosphorylated somewhat more strongly. Unexpectedly, we found that reconstitution of the transmembrane and cytoplasmic domains of EGFR in vesicles leads to a peculiar phenomenon in which kinase domains appear to be trapped between stacks of lipid bilayers. This artifactual trapping of kinases between membranes enhances an intrinsic functional asymmetry in the two tails in a dimer.
机译：表皮生长因子受体（EGFR）的〜230个残基的C末端尾巴在激活时被磷酸化。我们检查了这种磷酸化是否受尾巴中缺失的影响以及不对称活性EGFR二聚体中的两个尾巴是否被不同地磷酸化。如前所述，我们使用流式细胞仪监测了细胞中的自磷酸化，发现尾部的前约80个残基具有抑制作用。整个〜80个残基跨度对于自动抑制很重要，需要从形成二聚体的两种激酶中释放出来。这些结果是根据非活性激酶结构域的晶体结构来解释的，包括此处介绍的两个新结构。尾部其余部分的缺失不影响自身磷酸化，除了跨越Tyr 1086的六个残基片段对激活环磷酸化至关重要。二聚体中两个尾部的磷酸化是不对称的，活化剂尾部的磷酸化作用更强一些。出乎意料的是，我们发现囊泡中EGFR的跨膜结构和胞质结构域的重建导致了一种特殊的现象，即激酶结构域似乎被困在脂质双层的堆叠之间。膜之间激酶的这种人为捕获会增强二聚体两个尾部的固有功能不对称性。

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