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. 1998 Mar 16;17(6):1665–1674. doi: 10.1093/emboj/17.6.1665

Crystal structure of a cytokine-binding region of gp130.

J Bravo 1, D Staunton 1, J K Heath 1, E Y Jones 1
PMCID: PMC1170514  PMID: 9501088

Abstract

The structure of the cytokine-binding homology region of the cell surface receptor gp130 has been determined by X-ray crystallography at 2.0 A resolution. The beta sandwich structure of the two domains conforms to the topology of the cytokine receptor superfamily. This first structure of an uncomplexed receptor exhibits a similar L-shaped quaternary structure to that of ligand-bound family members and suggests a limited flexibility in relative domain orientation of some 3 degrees. The putative ligand-binding loops are relatively rigid, with a phenylalanine side chain similarly positioned to exposed aromatic residues implicated in ligand binding for other such receptors. The positioning and structure of the N-terminal portion of the polypeptide chain have implications for the structure and function of cytokine receptors, such as gp130, which contain an additional N-terminal immunoglobulin-like domain.

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Selected References

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  1. Barton G. J. ALSCRIPT: a tool to format multiple sequence alignments. Protein Eng. 1993 Jan;6(1):37–40. doi: 10.1093/protein/6.1.37. [DOI] [PubMed] [Google Scholar]
  2. Bork P., Downing A. K., Kieffer B., Campbell I. D. Structure and distribution of modules in extracellular proteins. Q Rev Biophys. 1996 May;29(2):119–167. doi: 10.1017/s0033583500005783. [DOI] [PubMed] [Google Scholar]
  3. Boulton T. G., Stahl N., Yancopoulos G. D. Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J Biol Chem. 1994 Apr 15;269(15):11648–11655. [PubMed] [Google Scholar]
  4. Cosman D. The hematopoietin receptor superfamily. Cytokine. 1993 Mar;5(2):95–106. doi: 10.1016/1043-4666(93)90047-9. [DOI] [PubMed] [Google Scholar]
  5. Cunningham B. C., Wells J. A. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science. 1989 Jun 2;244(4908):1081–1085. doi: 10.1126/science.2471267. [DOI] [PubMed] [Google Scholar]
  6. Ernst M., Gearing D. P., Dunn A. R. Functional and biochemical association of Hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells. EMBO J. 1994 Apr 1;13(7):1574–1584. doi: 10.1002/j.1460-2075.1994.tb06420.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fan Q. R., Mosyak L., Winter C. C., Wagtmann N., Long E. O., Wiley D. C. Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature. 1997 Sep 4;389(6646):96–100. doi: 10.1038/38028. [DOI] [PubMed] [Google Scholar]
  8. Feng D. F., Doolittle R. F. Progressive sequence alignment as a prerequisite to correct phylogenetic trees. J Mol Evol. 1987;25(4):351–360. doi: 10.1007/BF02603120. [DOI] [PubMed] [Google Scholar]
  9. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  10. Gearing D. P., Thut C. J., VandeBos T., Gimpel S. D., Delaney P. B., King J., Price V., Cosman D., Beckmann M. P. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 1991 Oct;10(10):2839–2848. doi: 10.1002/j.1460-2075.1991.tb07833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar]
  12. Hilton D. J., Hilton A. A., Raicevic A., Rakar S., Harrison-Smith M., Gough N. M., Begley C. G., Metcalf D., Nicola N. A., Willson T. A. Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction. EMBO J. 1994 Oct 17;13(20):4765–4775. doi: 10.1002/j.1460-2075.1994.tb06802.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hirota H., Yoshida K., Kishimoto T., Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4862–4866. doi: 10.1073/pnas.92.11.4862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Horsten U., Müller-Newen G., Gerhartz C., Wollmer A., Wijdenes J., Heinrich P. C., Grötzinger J. Molecular modeling-guided mutagenesis of the extracellular part of gp130 leads to the identification of contact sites in the interleukin-6 (IL-6).IL-6 receptor.gp130 complex. J Biol Chem. 1997 Sep 19;272(38):23748–23757. doi: 10.1074/jbc.272.38.23748. [DOI] [PubMed] [Google Scholar]
  15. Horsten U., Schmitz-Van de Leur H., Müllberg J., Heinrich P. C., Rose-John S. The membrane distal half of gp130 is responsible for the formation of a ternary complex with IL-6 and the IL-6 receptor. FEBS Lett. 1995 Feb 20;360(1):43–46. doi: 10.1016/0014-5793(95)00053-c. [DOI] [PubMed] [Google Scholar]
  16. Hudson K. R., Vernallis A. B., Heath J. K. Characterization of the receptor binding sites of human leukemia inhibitory factor and creation of antagonists. J Biol Chem. 1996 May 17;271(20):11971–11978. doi: 10.1074/jbc.271.20.11971. [DOI] [PubMed] [Google Scholar]
  17. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson D. J. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. doi: 10.1016/0092-8674(92)90634-o. [DOI] [PubMed] [Google Scholar]
  18. Jones T. A., Zou J. Y., Cowan S. W., Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A. 1991 Mar 1;47(Pt 2):110–119. doi: 10.1107/s0108767390010224. [DOI] [PubMed] [Google Scholar]
  19. Karow J., Hudson K. R., Hall M. A., Vernallis A. B., Taylor J. A., Gossler A., Heath J. K. Mediation of interleukin-11-dependent biological responses by a soluble form of the interleukin-11 receptor. Biochem J. 1996 Sep 1;318(Pt 2):489–495. doi: 10.1042/bj3180489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kishimoto T., Tanaka T., Yoshida K., Akira S., Taga T. Cytokine signal transduction through a homo- or heterodimer of gp130. Ann N Y Acad Sci. 1995 Sep 7;766:224–234. doi: 10.1111/j.1749-6632.1995.tb26670.x. [DOI] [PubMed] [Google Scholar]
  21. LeMaster D. M., Richards F. M. 1H-15N heteronuclear NMR studies of Escherichia coli thioredoxin in samples isotopically labeled by residue type. Biochemistry. 1985 Dec 3;24(25):7263–7268. doi: 10.1021/bi00346a036. [DOI] [PubMed] [Google Scholar]
  22. Liu J., Modrell B., Aruffo A., Marken J. S., Taga T., Yasukawa K., Murakami M., Kishimoto T., Shoyab M. Interleukin-6 signal transducer gp130 mediates oncostatin M signaling. J Biol Chem. 1992 Aug 25;267(24):16763–16766. [PubMed] [Google Scholar]
  23. 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 A. Science. 1996 Jul 26;273(5274):464–471. doi: 10.1126/science.273.5274.464. [DOI] [PubMed] [Google Scholar]
  24. McDonald N. Q., Panayotatos N., Hendrickson W. A. Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J. 1995 Jun 15;14(12):2689–2699. doi: 10.1002/j.1460-2075.1995.tb07269.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Merritt E. A., Murphy M. E. Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr D Biol Crystallogr. 1994 Nov 1;50(Pt 6):869–873. doi: 10.1107/S0907444994006396. [DOI] [PubMed] [Google Scholar]
  26. Mosley B., De Imus C., Friend D., Boiani N., Thoma B., Park L. S., Cosman D. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem. 1996 Dec 20;271(51):32635–32643. doi: 10.1074/jbc.271.51.32635. [DOI] [PubMed] [Google Scholar]
  27. Murakami M., Hibi M., Nakagawa N., Nakagawa T., Yasukawa K., Yamanishi K., Taga T., Kishimoto T. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993 Jun 18;260(5115):1808–1810. doi: 10.1126/science.8511589. [DOI] [PubMed] [Google Scholar]
  28. Paonessa G., Graziani R., De Serio A., Savino R., Ciapponi L., Lahm A., Salvati A. L., Toniatti C., Ciliberto G. Two distinct and independent sites on IL-6 trigger gp 130 dimer formation and signalling. EMBO J. 1995 May 1;14(9):1942–1951. doi: 10.1002/j.1460-2075.1995.tb07186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pennica D., Shaw K. J., Swanson T. A., Moore M. W., Shelton D. L., Zioncheck K. A., Rosenthal A., Taga T., Paoni N. F., Wood W. I. Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem. 1995 May 5;270(18):10915–10922. doi: 10.1074/jbc.270.18.10915. [DOI] [PubMed] [Google Scholar]
  30. Robinson R. C., Grey L. M., Staunton D., Vankelecom H., Vernallis A. B., Moreau J. F., Stuart D. I., Heath J. K., Jones E. Y. The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding. Cell. 1994 Jul 1;77(7):1101–1116. doi: 10.1016/0092-8674(94)90449-9. [DOI] [PubMed] [Google Scholar]
  31. Saito M., Yoshida K., Hibi M., Taga T., Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992 Jun 15;148(12):4066–4071. [PubMed] [Google Scholar]
  32. Saul F. A., Poljak R. J. Crystal structure of human immunoglobulin fragment Fab New refined at 2.0 A resolution. Proteins. 1992 Nov;14(3):363–371. doi: 10.1002/prot.340140305. [DOI] [PubMed] [Google Scholar]
  33. Savino R., Lahm A., Salvati A. L., Ciapponi L., Sporeno E., Altamura S., Paonessa G., Toniatti C., Ciliberto G. Generation of interleukin-6 receptor antagonists by molecular-modeling guided mutagenesis of residues important for gp130 activation. EMBO J. 1994 Mar 15;13(6):1357–1367. doi: 10.1002/j.1460-2075.1994.tb06389.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sheldrick G. M., Dauter Z., Wilson K. S., Hope H., Sieker L. C. The application of direct methods and Patterson interpretation to high-resolution native protein data. Acta Crystallogr D Biol Crystallogr. 1993 Jan 1;49(Pt 1):18–23. doi: 10.1107/S0907444992007364. [DOI] [PubMed] [Google Scholar]
  35. Simpson R. J., Hammacher A., Smith D. K., Matthews J. M., Ward L. D. Interleukin-6: structure-function relationships. Protein Sci. 1997 May;6(5):929–955. doi: 10.1002/pro.5560060501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Somers W., Stahl M., Seehra J. S. 1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling. EMBO J. 1997 Mar 3;16(5):989–997. doi: 10.1093/emboj/16.5.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Somers W., Ultsch M., De Vos A. M., Kossiakoff A. A. The X-ray structure of a growth hormone-prolactin receptor complex. Nature. 1994 Dec 1;372(6505):478–481. doi: 10.1038/372478a0. [DOI] [PubMed] [Google Scholar]
  38. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar]
  39. Stahl N., Farruggella T. J., Boulton T. G., Zhong Z., Darnell J. E., Jr, Yancopoulos G. D. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995 Mar 3;267(5202):1349–1353. doi: 10.1126/science.7871433. [DOI] [PubMed] [Google Scholar]
  40. Stuart D. I., Levine M., Muirhead H., Stammers D. K. Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 A. J Mol Biol. 1979 Oct 15;134(1):109–142. doi: 10.1016/0022-2836(79)90416-9. [DOI] [PubMed] [Google Scholar]
  41. Walter M. R., Windsor W. T., Nagabhushan T. L., Lundell D. J., Lunn C. A., Zauodny P. J., Narula S. K. Crystal structure of a complex between interferon-gamma and its soluble high-affinity receptor. Nature. 1995 Jul 20;376(6537):230–235. doi: 10.1038/376230a0. [DOI] [PubMed] [Google Scholar]
  42. Wang Y., Nesbitt J. E., Fuentes N. L., Fuller G. M. Molecular cloning and characterization of the rat liver IL-6 signal transducing molecule, gp130. Genomics. 1992 Nov;14(3):666–672. doi: 10.1016/s0888-7543(05)80166-1. [DOI] [PubMed] [Google Scholar]
  43. Ward L. D., Howlett G. J., Discolo G., Yasukawa K., Hammacher A., Moritz R. L., Simpson R. J. High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130. J Biol Chem. 1994 Sep 16;269(37):23286–23289. [PubMed] [Google Scholar]
  44. Wells J. A., Cunningham B. C., Fuh G., Lowman H. B., Bass S. H., Mulkerrin M. G., Ultsch M., deVos A. M. The molecular basis for growth hormone-receptor interactions. Recent Prog Horm Res. 1993;48:253–275. [PubMed] [Google Scholar]
  45. Xu G. Y., Yu H. A., Hong J., Stahl M., McDonagh T., Kay L. E., Cumming D. A. Solution structure of recombinant human interleukin-6. J Mol Biol. 1997 May 2;268(2):468–481. doi: 10.1006/jmbi.1997.0933. [DOI] [PubMed] [Google Scholar]
  46. Yamasaki K., Naito S., Anaguchi H., Ohkubo T., Ota Y. Solution structure of an extracellular domain containing the WSxWS motif of the granulocyte colony-stimulating factor receptor and its interaction with ligand. Nat Struct Biol. 1997 Jun;4(6):498–504. doi: 10.1038/nsb0697-498. [DOI] [PubMed] [Google Scholar]
  47. Yawata H., Yasukawa K., Natsuka S., Murakami M., Yamasaki K., Hibi M., Taga T., Kishimoto T. Structure-function analysis of human IL-6 receptor: dissociation of amino acid residues required for IL-6-binding and for IL-6 signal transduction through gp130. EMBO J. 1993 Apr;12(4):1705–1712. doi: 10.1002/j.1460-2075.1993.tb05815.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yoshida K., Taga T., Saito M., Suematsu S., Kumanogoh A., Tanaka T., Fujiwara H., Hirata M., Yamagami T., Nakahata T. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):407–411. doi: 10.1073/pnas.93.1.407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. de Vos A. M., Ultsch M., Kossiakoff A. A. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 1992 Jan 17;255(5042):306–312. doi: 10.1126/science.1549776. [DOI] [PubMed] [Google Scholar]

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