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An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation

Nature Structural Biology volume 5, pages 993–1004 (1998)Cite this article

Abstract

Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor activation. The crystal structure of the extracellular domain of EPOR bound to an inactive (antagonist) peptide at 2.7 Å resolution has unexpectedly revealed that dimerization still occurs, but the orientation between receptor molecules is altered relative to active (agonist) peptide complexes. Comparison of the biological properties of agonist and antagonist EMPs with EPO suggests that the extracellular domain orientation is tightly coupled to the cytoplasmic signaling events and, hence, provides valuable new insights into the design of synthetic ligands for EPOR and other cytokine receptors.

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Figure 1: Receptor cross linking and dimerization analysis.
Figure 2: Bioactivity of EMP1 and EMP33 a, Ligand-induced protein tyrosine phosphorylation.
Figure 3: Activation of signaling through native and chimeric EPOR.
Figure 4: Identification of EMP33 as an antagonist of the EPOR.
Figure 5: Superposition of an active and inactive EPOR assembly.
Figure 6: Stereo representation of the superposition between the two EMP33 peptides in EBP–EMP33 complex structure.
Figure 7: The hydrophobic interaction surface between EBP and EMP peptides.

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Acknowledgements

This work was supported in part by the NIH (I.A.W., M.A.G. and S.P.), and a New Jersey State Commission on Cancer Research grant (C.D.K.). O. L. was supported by a Rueff-Wormser postdoctoral fellowship and K.D.L. was supported by the N.I.H. Medical Scientist Training Program and the Program in Biological Sciences at U.C.S.F. We thank J. Tullai and F. McMahon for technical assistance, K. Hoey for peptide synthesis, H. Lashuel and J. Kelly for peptide ultracentrifugation and R.M. Stroud, J.A. Wells, S.L. Schreiber and D.C. Wiley for helpful discussions. This is publication 11174-MB from the Scripps Research Institute.

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Author notes

  1. Oded Livnah

    Present address: Department of Biological Chemistry, Institute of Life Sciences, The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel

  2. Enrico A. Stura

    Present address: Departement d'Ingenierie et d'Etude des Proteines, BAT 152 C.E.A./SACLAY, 91191, Gif sur Yvette Cedex, France

Authors and Affiliations

  1. Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, 92037, California, USA

    Oded Livnah, Enrico A. Stura & Ian A. Wilson

  2. R.W. Johnson Pharmaceutical Research Institute, Drug Discovery Research, 1000 Route 202, Box 300, Raritan, 08869, New Jersey, USA

    Dana L. Johnson, Francis X. Farrell, Francis P. Barbone & Linda K. Jolliffe

  3. Gladstone Institute of Virology and Immunology, San Francisco, 94141, California, USA

    Mark A. Goldsmith

  4. Department of Medicine, School of Medicine, UCSF, San Francisco, 94143, California, USA

    Yun You, Kathleen D. Liu & Mark A. Goldsmith

  5. Robert Wood Johnson Medical School-UMDNJ, 675 Hoes Lane, Piscataway, 08854 , New Jersey, USA

    Wen He, Christopher D. Krause & Sidney Pestka

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Correspondence to Linda K. Jolliffe or Ian A. Wilson.

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Livnah, O., Johnson, D., Stura, E. et al. An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation. Nat Struct Mol Biol 5, 993–1004 (1998). https://doi.org/10.1038/2965

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