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Molecular Architecture of a Network of Potential Intracellular EGFR Modulators: ARNO, CaM, Phospholipids, and the Juxtamembrane Segment.
Structure ( IF 5.7 ) Pub Date : 2019-11-25 , DOI: 10.1016/j.str.2019.11.001
Aldino Viegas 1 , Dongsheng M Yin 2 , Jan Borggräfe 3 , Thibault Viennet 1 , Marcel Falke 4 , Anton Schmitz 2 , Michael Famulok 2 , Manuel Etzkorn 3
Affiliation  

Epidermal growth factor receptors (EGFRs) are central cellular signaling interfaces whose misregulation is related to several severe diseases. Although ligand binding to the extracellular domain is the most obvious regulatory element, also intracellular factors can act as modulators of EGFR activity. The juxtamembrane (JM) segment seems to be the receptor's key interaction interface of these cytoplasmic factors. However, only a limited number of cytoplasmic EGFR modulators are known and a comprehensive understanding of their mode of action is lacking. Here, we report ARNO, a member of the cytohesin family, as another JM-binding protein and structurally characterize the ARNO-EGFR interaction interface. We reveal that its binding mode displays common features and distinct differences with JM's interaction with calmodulin and anionic phospholipids. Furthermore, we show that each interaction can be modulated by additional factors, generating a distinctly regulated network of possible EGFR modulators acting on the intracellular domain of the receptor.

中文翻译:

潜在的细胞内EGFR调节剂网络的分子结构:ARNO,CaM,磷脂和近膜节。

表皮生长因子受体(EGFR)是中央细胞信号传导接口,其失调与几种严重疾病有关。尽管配体与细胞外结构域的结合是最明显的调节元件,但细胞内因子也可以充当EGFR活性的调节剂。近膜(JM)节段似乎是这些细胞质因子受体的关键相互作用界面。然而,仅有限数量的细胞质EGFR调节剂是已知的,并且对其作用方式缺乏全面的了解。在这里,我们报道细胞粘附素家族的成员ARNO,作为另一种JM结合蛋白,在结构上表征了ARNO-EGFR相互作用的界面。我们发现它的绑定模式显示了与JM'的共同特征和明显差异 与钙调蛋白和阴离子磷脂的相互作用。此外,我们表明,每种相互作用都可以通过其他因素来调节,从而产生作用于受体细胞内结构域的可能的EGFR调节剂的明显调控的网络。
更新日期:2019-11-26
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