Proteopedia

3c9a

High Resolution Crystal Structure of Argos bound to the EGF domain of SpitzHigh Resolution Crystal Structure of Argos bound to the EGF domain of Spitz

Structural highlights

3c9a is a 4 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:argos, Aos, gil, sty (Drosophila melanogaster), spi (Drosophila melanogaster)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GIL_DROME] Regulates cell determination; development of ommatidia and optic lobe. Is a signaling molecule involved in the process of axon pathfinding in the eye. Part of the Ras pathway regulating programmed cell death in pupal eyes; activated by lozenge (lz). Antagonist for the Egfr receptor (gurken). Inhibits Egfr signaling without interacting directly with the receptor, but instead by sequestering the Egfr-activating ligand spitz (spi).[1] [2] [3] [4] [5] [6] [SPITZ_DROME] Ligand for the EGF receptor (Gurken). Involved in a number of unrelated developmental choices, for example, dorsal-ventral axis formation, glial migration, sensory organ determination, and muscle development. It is required for photoreceptor determination.[7]

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Structural basis for EGFR ligand sequestration by Argos.,Klein DE, Stayrook SE, Shi F, Narayan K, Lemmon MA Nature. 2008 Jun 26;453(7199):1271-5. Epub 2008 May 25. PMID:18500331[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Kretzschmar D, Brunner A, Wiersdorff V, Pflugfelder GO, Heisenberg M, Schneuwly S. Giant lens, a gene involved in cell determination and axon guidance in the visual system of Drosophila melanogaster. EMBO J. 1992 Jul;11(7):2531-9. PMID:1628618
  2. ↑ Freeman M, Klambt C, Goodman CS, Rubin GM. The argos gene encodes a diffusible factor that regulates cell fate decisions in the Drosophila eye. Cell. 1992 Jun 12;69(6):963-75. PMID:1606617
  3. ↑ Okano H, Hayashi S, Tanimura T, Sawamoto K, Yoshikawa S, Watanabe J, Iwasaki M, Hirose S, Mikoshiba K, Montell C. Regulation of Drosophila neural development by a putative secreted protein. Differentiation. 1992 Dec;52(1):1-11. PMID:1286772
  4. ↑ Sawamoto K, Taguchi A, Hirota Y, Yamada C, Jin MH, Okano H. Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway. Cell Death Differ. 1998 Apr;5(4):262-70. PMID:10200472 doi:http://dx.doi.org/10.1038/sj.cdd.4400342
  5. ↑ Klein DE, Nappi VM, Reeves GT, Shvartsman SY, Lemmon MA. Argos inhibits epidermal growth factor receptor signalling by ligand sequestration. Nature. 2004 Aug 26;430(7003):1040-4. PMID:15329724 doi:http://dx.doi.org/10.1038/nature02840
  6. ↑ Wildonger J, Sosinsky A, Honig B, Mann RS. Lozenge directly activates argos and klumpfuss to regulate programmed cell death. Genes Dev. 2005 May 1;19(9):1034-9. PMID:15879554 doi:http://dx.doi.org/19/9/1034
  7. ↑ Freeman M. The spitz gene is required for photoreceptor determination in the Drosophila eye where it interacts with the EGF receptor. Mech Dev. 1994 Oct;48(1):25-33. PMID:7833286
  8. ↑ Klein DE, Stayrook SE, Shi F, Narayan K, Lemmon MA. Structural basis for EGFR ligand sequestration by Argos. Nature. 2008 Jun 26;453(7199):1271-5. Epub 2008 May 25. PMID:18500331 doi:10.1038/nature06978

3c9a, resolution 1.60Å

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