3CA7

High Resolution Crystal Structure of the EGF domain of Spitz

3CA7 の概要

• エントリーDOI: 10.2210/pdb3ca7/pdb
• 分子名称: Protein spitz (2 entities in total)
• 機能のキーワード: spitz, argos, egf, developmental protein, differentiation, egf-like domain, endoplasmic reticulum, glycoprotein, golgi apparatus, membrane, neurogenesis, transmembrane, hormone-signaling protein complex, hormone/signaling protein
• 由来する生物種: Drosophila melanogaster (Fruit fly)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: Q01083
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 6012.86

構造登録者

Klein, D.E.,Stayrook, S.E.,Lemmon, M.A. (登録日: 2008-02-19, 公開日: 2008-05-20, 最終更新日: 2024-11-20)

主引用文献

Klein, D.E.,Stayrook, S.E.,Shi, F.,Narayan, K.,Lemmon, M.A.
Structural basis for EGFR ligand sequestration by Argos.
Nature, 453:1271-1275, 2008

PubMed Abstract: 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-beta 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.

PubMed: 18500331
DOI: 10.1038/nature06978

実験手法

X-RAY DIFFRACTION (1.5 Å)