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Structural basis for EGFR ligand sequestration by Argos

机译：Argos隔离EGFR配体的结构基础

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摘要

Members of the epidermal growth factor receptor (EGFR) or ErbB/ HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-β family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.
机译：表皮生长因子受体（EGFR）或ErbB / HER家族的成员及其活化配体是各种发育过程的重要调节剂。这些受体的不适当活化是许多人类癌症的关键特征，并且其逆转是重要的临床目标。果蝇中发现了一种天然的EGFR信号传导拮抗剂，称为Argos。先前我们证明了Argos通过直接结合（螯合）激活EGFR的生长因子配体发挥功能。在这里，我们描述了与EGFR配体结合的Argos的1.6-A分辨率晶体结构。与预期相反，Argos不包含类似EGF的域。相反，三个紧密相关的结构域（类似于三指毒素折叠）在结合的EGF配体周围形成钳状结构。尽管在结构上与受体无关，但是Argos通过使用两部分结合表面捕获EGF来模仿EGFR。各个Argos结构域与转化生长因子-β家族受体的胞外配体结合区具有意想不到的结构相似性。 Argos的三结构域钳位也类似于尿激酶型纤溶酶原激活剂（uPA）受体，该受体使用类似的机制吞噬uPA的EGF样模块。我们的结果表明，在其他特征较弱的结构同系物中可能存在未被发现的Argos哺乳动物对应物。此外，此处介绍的结构定义了设计人工EGF替代蛋白的要求，这些蛋白将是有价值的抗癌治疗剂。

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  • 来源
    《Nature》 |2008年第7198期|1271-1275|共5页
  • 作者

    Daryl E. Klein; Steven E. Stayrook; Fumin Shi; Kartik Narayan; Mark A. Lemmon;

  • 作者单位

    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA;

    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA;

    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA;

    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA;

    Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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