The structure, organization, activation and plasticity of the erythropoietin receptor

Current Opinion in Structural Biology

Volumn 9, Issue 6, 1999, Pages 696-704

  Wilson, Ian A ^a   Jolliffe, Linda K ^b  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR; LIGAND; PROTEIN SUBUNIT; RECEPTOR BLOCKING AGENT;

BINDING SITE; COMPLEX FORMATION; DIMERIZATION; LIGAND BINDING; MOLECULAR RECOGNITION; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN PROTEIN INTERACTION; REVIEW;

EID: 0032783793     PISSN: 0959440X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-440X(99)00032-9     Document Type: Review

References (59)

1. Goldsmith M.A., Mikami A., You Y., Liu K.D., Thomas L., Pharr P., Longmore G.D. Absence of cytokine receptor-dependent specificity in red blood cell differentiation in vivo. Proc Natl Acad Sci USA. 95:1998;7006-7011.
2. Krantz S.B. Erythropoietin. Blood. 77:1991;419-434.
3. Bazan J.F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA. 87:1990;6934-6938.
4. Livnah O., Stura E.A., Johnson D.L., Middleton S.A., Mulcahy L.S., Wrighton N.C., Dower W.J., Jolliffe L.K., Wilson I.A. Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2. 8 Å. Science. 273:1996;464-471.
5. Wrighton N.C., Farrell F.X., Chang R., Kashyap A.K., Barbone F.P., Mulcahy L.S., Johnson D.L., Barrett R.W., Jolliffe L.K., Dower W.J. Small peptides as potent mimetics of the protein hormone erythropoietin. Science. 273:1996;458-463.
6. McConnell S.J., Dinh T., Le M.-H., Brown S.J., Becherer K., Blumeyer K., Kautzer C., Axelrod F., Spinella D.G. Isolation of erythropoietin receptor agonist peptides using evolved phage libraries. Biol Chem. 379:1998;1279-1286.
7. Cwirla S.S., Balasubramanian P., Duffin D.J., Wagstrom C.R., Gates C.M., Singer S.C., Davis A.M., Tansik R.L., Mattheakis L.C., Boytos C.M.et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science. 276:1997;1696-1699.
8. Kimura T., Kaburaki H., Miyamoto S., Katayama J., Watanabe Y. Discovery of a novel thrombopoietin mimic agonist peptide. J Biochem. 122:1997;1046-1051.
9. Tian S.S., Lamb P., King A.G., Miller S.G., Kessler L., Luengo J.I., Averill L., Johnson R.K., Gleason J.G., Pelus L.M.et al. A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor. Science. 281:1998;257-259.
10. Kimura T., Kaburaki H., Tsujino T., Ikeda Y., Kato H., Watanabe Y. A non-peptide compound which can mimic the effect of thrombopoietin via c-Mpl. FEBS Lett. 428:1998;250-254.
11. Watowich S.S., Hilton D.J., Lodish H.F. Activation and inhibition of erythropoietin receptor function: role of receptor dimerization. Mol Cell Biol. 14:1994;3535-3549.
12. Witthuhn B.A., Silvennoinen O., Miura O., Lai K.S., Cwik C., Liu E.T., Ihle J.N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 14:1994;153-157.
13. -/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 98:1999;181-191.
14. D'Andrea A.D., Yoshimura A., Youssoufian H., Zon L.I., Koo J.W., Lodish H.F. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 11:1991;1980-1987.
15. Miura O., Ihle J.N. Dimer- and oligomerization of the erythropoietin receptor by disulfide bond formation and significance of the region near the WSXWS motif in intracellular transport. Arch Biochem Biophys. 306:1993;200-208.
16. Yoshimura A., Longmore G., Lodish H.F. Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature. 348:1990;647-649.
17. Watowich S.S., Yoshimura A., Longmore G.D., Hilton D.J., Yoshimura Y., Lodish H.F. Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci USA. 89:1992;2140-2144.
18. Elliott S., Lorenzini T., Yanagihara D., Chang D., Elliott G. Activation of the erythropoietin (EPO) receptor by bivalent anti-EPO receptor antibodies. J Biol Chem. 271:1996;24691-24697.
19. Schneider H., Chaovapong W., Matthews D.J., Karkaria C., Cass R.T., Zhan H., Boyle M., Lorenzini T., Elliott S.G., Giebel L.B. Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors. Blood. 89:1997;473-482.
20. Livnah O., Johnson D.L., Stura E.A., Farrell F.X., Barbone F.P., You Y., Liu K.D., Goldsmith M.A., He W., Krause C.et al. An antagonist peptide-EPO receptor complex: receptor dimerization is not sufficient for activation. Nat Struct Biol. 5:1998;993-1004. A Tyr4 to dibromo-Tyr4 substitution surprisingly changed the EMP peptide mimetic from an agonist to antagonist. This can be correlated with a structural change from a symmetric dimer (180°) to an asymmetric dimer assembly (165°).
21. Livnah O., Stura E.A., Middleton S.A., Johnson D.L., Jolliffe L.K., Wilson I.A. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science. 283:1999;987-990. The unexpected observation of a dimer in crystals formed from the self-association of the two receptor binding sites suggested that the EPOR may exist as an unliganded dimer on the cell surface. This would reduce the background for any spontaneous signaling.
22. Syed R.S., Reid S.W., Li C., Cheetham J.C., Aoki K.H., Liu B., Zhan H., Osslund T.D., Chirino A.J., Zhang J.et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature. 395:1998;511-516. Substantial mutagenesis in both EPO and EPOR were required to produce a high-resolution crystal structure of EPOR with its natural ligand. The high (nanomolar) and low (micromolar) affinity site 1 and site 2 interfaces bury the two 'hot spot' residues, Phe93 and Phe205, in a central hydrophobic core, which is surrounded by hydrophilic residues. The dimer assembly is very asymmetric, with the receptors arranged at 120° relative to one another.
23. Remy I., Wilson I.A., Michnick S.W. Erythropoietin receptor activation by a ligand-induced conformation change. Science. 283:1999;990-993. Receptor dimerization on the cell surface was probed using a protein fragment complementation assay. In this way, by altering the ligand binder and receptor lengths, different dimeric assemblies were identified on the cell surface that provide evidence of the unliganded dimer receptor structures, as well as biological evidence on the cell surface for the different arrangement of receptors as seen in the unliganded and liganded crystal structures.
24. Fisher J.W. Erythropoietin: physiologic and pharmacologic aspects. Proc Soc Exp Biol Med. 216:1997;358-369.
25. Fisher J.W. A quest for erythropoietin over nine decades. Annu Rev Pharmacol Toxicol. 38:1998;1-20.
26. Lacombe C., Mayeux P. Biology of erythropoietin. Haematologica. 83:1998;724-732.
27. Lacombe C., Mayeux P. The molecular biology of erythropoietin. Nephrol Dial Transplant. 14:1999;22-28.
28. Wrighton N.C., Balasubramanian P., Barbone F.P., Kashyap A.K., Farrell F.X., Jolliffe L.K., Barrett R.W., Dower W.J. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat Biotechnol. 15:1997;1261-1265.
29. Johnson D.L., Farrell F.X., Barbone F.P., McMahon F.J., Tullai J., Kroon D., Freedy J., Zivin R.A., Mulcahy L.S., Jolliffe L.K. Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity. Chem Biol. 4:1997;939-950.
30. Dower W.J. Targeting growth factor and cytokine receptors with recombinant peptide libraries. Curr Opin Chem Biol. 2:1998;328-334.
31. Johnson D.L., Farrell F.X., Barbone F.P., McMahon F.J., Tullai J., Hoey K., Livnah O., Wrighton N.C., Middleton S.A., Loughney D.A.et al. Identification of a 13 amino acid peptide mimetic of erythropoietin and description of amino acids critical for the mimetic activity of EMP1. Biochemistry. 37:1998;3699-3710.
32. Zhan H., Liu B., Reid S.W., Aoki K.H., Li C., Syed R.S., Karkaria C., Koe G., Sitney K., Hayenga K.et al. Engineering a soluble extracellular erythropoietin receptor (EPObp) in Pichia pastoris to eliminate microheterogeneity, and its complex with erythropoietin. Protein Eng. 12:1999;505-513. A fascinating look at the engineering that was required to produce sufficient amounts of the soluble, purified EPO receptor for co-crystallization with EPO.
33. de Vos A.M., Ultsch M., Kossiakoff A.A. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 255:1992;306-312.
34. Philo J.S., Aoki K.H., Arakawa T., Narhi L.O., Wen J. Dimerization of the extracellular domain of the erythropoietin (EPO) receptor by EPO: one high-affinity and one low-affinity interaction. Biochemistry. 35:1996;1681-1691.
35. Sytkowski A.J., Lunn E.D., Risinger M.A., Davis K.L. An erythropoietin fusion protein comprised of identical repeating domains exhibits enhanced biological properties. J Biochem. 274:1999;24773-24778.
36. Qiu H., Belanger A., Yoon H.W., Bunn H.F. Homodimerization restores biological activity to an inactive erythropoietin mutant. J Biochem. 273:1998;11173-11176.
37. Cheetham J.C., Smith D.M., Aoki K.H., Stevenson J.L., Hoeffel T.J., Syed R.S., Egrie J., Harvey T.S. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol. 5:1998;861-866. A mutant version of erythropoietin that has improved solubility was engineered for this NMR study, which provided the first look at the unliganded EPO structure. To date, EPO by itself has not been crystallized after many years of effort.
38. Naismith J.H., Brandhuber B.J., Devine T.Q., Sprang S.R. Seeing double: crystal structures of the type I TNF receptor. J Mol Recog. 9:1995;113-117.
39. Naismith J.H., Devine T.Q., Kohno T., Sprang S.R. Structures of the extracellular domain of the type 1 tumor necrosis factor receptor. Structure. 4:1996;1251-1262.
40. Luo R.Z.-T., Beniac D.R., Fernandes A., Yip C.C., Ottensmeyer F.P. Quaternary structure of the insulin-insulin receptor complex. Science. 285:1999;1077-1080.
41. Woodcock J.M., McClure B.J., Stomski F.C., Elliott M.J., Bagley C.J., Lopez A.F. The human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor exists as a preformed receptor complex that can be activated by GM-CSF, interleukin-3, or interleukin-5. Blood. 90:1997;3005-3017.
42. Sawada K., Krantz S.B., Sawyer S.T., Civin C.I. Quantitation of specific binding of erythropoietin to human erythroid colony-forming cells. J Cell Physiol. 137:1988;337-345.
43. Sawada K., Krantz S.B., Kans J.S., Dessypris E.N., Sawyer S., Glick A.D., Civin C.I. Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin. J Clin Invest. 80:1987;357-366.
44. Broudy V.C., Lin N., Brice M., Nakamoto B., Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 77:1991;2583-2590.
45. Middleton S.A., Barbone F.P., Johnson D.L., Thurmond R.L., You Y., McMahon F.J., Jin R., Livnah O., Tullai J., Farrell F.L.et al. Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide. J Biol Chem. 274:1999;14163-14169. A key mutagenesis study that shows that Phe93 and Phe205 are important for both EMP1 and EPO binding, whereas Met150 is important for EMP1, but not EPO, binding.
46. Clackson T., Wells J.A. A hot spot of binding energy in a hormone-receptor interface. Science. 267:1995;383-386.
47. Hage T., Sebald W., Reinemer P. Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. Cell. 97:1999;271-281.
48. Jolliffe L.K., Middleton S.A., Barbone F.P., Johnson D.L., McMahon F.J., Lee W.H., Gruninger R.H., Mulcahy L.S. Erythropoietin receptor: application in drug development. Nephrol Dial Transplant. 2:1995;28-34.
49. Middleton S.A., Johnson D.L., Jin R., McMahon F.J., Collins A., Tullai J., Gruninger R.H., Jolliffe L.K., Mulcahy L.S. Identification of a critical ligand binding determinant of the human erythropoietin receptor. Evidence for common ligand binding motifs in the cytokine receptor family. J Biol Chem. 271:1996;14045-14054.
50. Wells J.A., de Vos A.M. Hematopoietic receptor complexes. Annu Rev Biochem. 65:1996;609-634.
51. Fields B.A., Goldbaum F.A., Ysern X., Poljak R.J., Mariuzza R.A. Molecular basis of antigen mimicry by an anti-idiotope. Nature. 374:1995;739-742.
52. Deisenhofer J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-Å resolution. Biochemistry. 20:1981;2361-2370.
53. Sauer-Eriksson A.E., Kleywegt G.J., Uhlen M., Jones T.A. Crystal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG. Structure. 3:1995;265-278.
54. Corper A.L., Sohi M.K., Bonagura V.R., Steinitz M., Jefferis R., Feinstein A., Beale D., Taussig M.J., Sutton B.J. Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction. Nat Struct Biol. 4:1997;374-381.
55. Burmeister W.P., Huber A.H., Bjorkman P.J. Crystal structure of the complex of rat neonatal Fc receptor with Fc. Nature. 372:1994;379-383.
56. Garcia K.C., Degano M., Pease L.R., Huang M., Peterson P.A., Teyton L., Wilson I.A. Structural basis of plasticity in T cell receptor recognition of a self-peptide-MHC antigen. Science. 279:1998;1166-1172.
57. Kraulis P.J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J Appl Crystallogr. 24:1991;946-950.
58. Merrit E.A., Murphy M.E.P. Raster3D Version 2.0- a program for photorealistic molecular graphics. Acta Crystallogr. 50:1994;869-873.
59. Nicholls A., Bharadwaj R., Honig B. GRASP: graphical representation and analysis of surface properties. Biophys J. 64:1993;166-167.