Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Sep 12;92(19):8579–8583. doi: 10.1073/pnas.92.19.8579

D1 cap region involved in the receptor recognition and neural cell survival activity of human ciliary neurotrophic factor.

M Inoue 1, C Nakayama 1, K Kikuchi 1, T Kimura 1, Y Ishige 1, A Ito 1, M Kanaoka 1, H Noguchi 1
PMCID: PMC41009  PMID: 7567978

Abstract

Human ciliary neurotrophic factor (hCNTF), which promotes the cell survival and differentiation of motor and other neurons, is a protein belonging structurally to the alpha-helical cytokine family. hCNTF was subjected to three-dimensional structure modeling and site-directed mutagenesis to analyze its structure-function relationship. The replacement of Lys-155 with any other amino acid residue resulted in abolishment of neural cell survival activity, and some of the Glu-153 mutant proteins had 5- to 10-fold higher biological activity. The D1 cap region (around the boundary between the CD loop and helix D) of hCNTF, including both Glu-153 and Lys-155, was shown to play a key role in the biological activity of hCNTF as one of the putative receptor-recognition sites. In this article, the D1 cap region of the 4-helix-bundle proteins is proposed to be important in receptor recognition and biological activity common to alpha-helical cytokine proteins reactive with gp130, a component protein of the receptors.

Full text

PDF
8579

Images in this article

8582Fig. 4
on p.8582

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arakawa Y., Sendtner M., Thoenen H. Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J Neurosci. 1990 Nov;10(11):3507–3515. doi: 10.1523/JNEUROSCI.10-11-03507.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bazan J. F. Neuropoietic cytokines in the hematopoietic fold. Neuron. 1991 Aug;7(2):197–208. doi: 10.1016/0896-6273(91)90258-2. [DOI] [PubMed] [Google Scholar]
  3. Boulay J. L., Paul W. E. Hematopoietin sub-family classification based on size, gene organization and sequence homology. Curr Biol. 1993 Sep 1;3(9):573–581. doi: 10.1016/0960-9822(93)90002-6. [DOI] [PubMed] [Google Scholar]
  4. Brakenhoff J. P., de Hon F. D., Fontaine V., ten Boekel E., Schooltink H., Rose-John S., Heinrich P. C., Content J., Aarden L. A. Development of a human interleukin-6 receptor antagonist. J Biol Chem. 1994 Jan 7;269(1):86–93. [PubMed] [Google Scholar]
  5. Cunningham B. C., Henner D. J., Wells J. A. Engineering human prolactin to bind to the human growth hormone receptor. Science. 1990 Mar 23;247(4949 Pt 1):1461–1465. doi: 10.1126/science.247.4949.1461. [DOI] [PubMed] [Google Scholar]
  6. Davis S., Aldrich T. H., Valenzuela D. M., Wong V. V., Furth M. E., Squinto S. P., Yancopoulos G. D. The receptor for ciliary neurotrophic factor. Science. 1991 Jul 5;253(5015):59–63. doi: 10.1126/science.1648265. [DOI] [PubMed] [Google Scholar]
  7. Fuh G., Cunningham B. C., Fukunaga R., Nagata S., Goeddel D. V., Wells J. A. Rational design of potent antagonists to the human growth hormone receptor. Science. 1992 Jun 19;256(5064):1677–1680. doi: 10.1126/science.256.5064.1677. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Hagg T., Quon D., Higaki J., Varon S. Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS. Neuron. 1992 Jan;8(1):145–158. doi: 10.1016/0896-6273(92)90116-u. [DOI] [PubMed] [Google Scholar]
  10. Hercus T. R., Bagley C. J., Cambareri B., Dottore M., Woodcock J. M., Vadas M. A., Shannon M. F., Lopez A. F. Specific human granulocyte-macrophage colony-stimulating factor antagonists. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5838–5842. doi: 10.1073/pnas.91.13.5838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ip N. Y., Li Y. P., van de Stadt I., Panayotatos N., Alderson R. F., Lindsay R. M. Ciliary neurotrophic factor enhances neuronal survival in embryonic rat hippocampal cultures. J Neurosci. 1991 Oct;11(10):3124–3134. doi: 10.1523/JNEUROSCI.11-10-03124.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  14. Kruse N., Tony H. P., Sebald W. Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement. EMBO J. 1992 Sep;11(9):3237–3244. doi: 10.1002/j.1460-2075.1992.tb05401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Layton J. E., Morstyn G., Fabri L. J., Reid G. E., Burgess A. W., Simpson R. J., Nice E. C. Identification of a functional domain of human granulocyte colony-stimulating factor using neutralizing monoclonal antibodies. J Biol Chem. 1991 Dec 15;266(35):23815–23823. [PubMed] [Google Scholar]
  16. Li X., Rock F., Chong P., Cockle S., Keating A., Ziltener H., Klein M. Structure-function analysis of the C-terminal segment of human interleukin-6. J Biol Chem. 1993 Oct 25;268(30):22377–22384. [PubMed] [Google Scholar]
  17. Lindsay R. M. Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor. Neurobiol Aging. 1994 Mar-Apr;15(2):249–251. doi: 10.1016/0197-4580(94)90124-4. [DOI] [PubMed] [Google Scholar]
  18. Lindsay R. M., Wiegand S. J., Altar C. A., DiStefano P. S. Neurotrophic factors: from molecule to man. Trends Neurosci. 1994 May;17(5):182–190. doi: 10.1016/0166-2236(94)90099-x. [DOI] [PubMed] [Google Scholar]
  19. Masiakowski P., Liu H. X., Radziejewski C., Lottspeich F., Oberthuer W., Wong V., Lindsay R. M., Furth M. E., Panayotatos N. Recombinant human and rat ciliary neurotrophic factors. J Neurochem. 1991 Sep;57(3):1003–1012. doi: 10.1111/j.1471-4159.1991.tb08250.x. [DOI] [PubMed] [Google Scholar]
  20. Mitsumoto H., Ikeda K., Holmlund T., Greene T., Cedarbaum J. M., Wong V., Lindsay R. M. The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann Neurol. 1994 Aug;36(2):142–148. doi: 10.1002/ana.410360205. [DOI] [PubMed] [Google Scholar]
  21. Mitsumoto H., Ikeda K., Klinkosz B., Cedarbaum J. M., Wong V., Lindsay R. M. Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science. 1994 Aug 19;265(5175):1107–1110. doi: 10.1126/science.8066451. [DOI] [PubMed] [Google Scholar]
  22. Negro A., Corona G., Bigon E., Martini I., Grandi C., Skaper S. D., Callegaro L. Synthesis, purification, and characterization of human ciliary neuronotrophic factor from E. coli. J Neurosci Res. 1991 Jun;29(2):251–260. doi: 10.1002/jnr.490290216. [DOI] [PubMed] [Google Scholar]
  23. Nesbitt J. E., Fuller G. M. Differential regulation of interleukin-6 receptor and gp130 gene expression in rat hepatocytes. Mol Biol Cell. 1992 Jan;3(1):103–112. doi: 10.1091/mbc.3.1.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nishi R. Neurotrophic factors: two are better than one. Science. 1994 Aug 19;265(5175):1052–1053. doi: 10.1126/science.8066443. [DOI] [PubMed] [Google Scholar]
  25. Panayotatos N., Radziejewska E., Acheson A., Pearsall D., Thadani A., Wong V. Exchange of a single amino acid interconverts the specific activity and gel mobility of human and rat ciliary neurotrophic factors. J Biol Chem. 1993 Sep 5;268(25):19000–19003. [PubMed] [Google Scholar]
  26. 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]
  27. Savino R., Lahm A., Giorgio M., Cabibbo A., Tramontano A., Ciliberto G. Saturation mutagenesis of the human interleukin 6 receptor-binding site: implications for its three-dimensional structure. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4067–4071. doi: 10.1073/pnas.90.9.4067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sendtner M., Kreutzberg G. W., Thoenen H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature. 1990 May 31;345(6274):440–441. doi: 10.1038/345440a0. [DOI] [PubMed] [Google Scholar]
  29. Sendtner M., Schmalbruch H., Stöckli K. A., Carroll P., Kreutzberg G. W., Thoenen H. Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy. Nature. 1992 Aug 6;358(6386):502–504. doi: 10.1038/358502a0. [DOI] [PubMed] [Google Scholar]
  30. Tymms M. J., McInnes B., Waine G. J., Cheetham B. F., Linnane A. W. Functional significance of amino acid residues within conserved hydrophilic regions in human interferons-alpha. Antiviral Res. 1989 Aug;12(1):37–47. doi: 10.1016/0166-3542(89)90066-1. [DOI] [PubMed] [Google Scholar]
  31. Varon S., Manthorpe M., Adler R. Cholinergic neuronotrophic factors: I. Survival, neurite outgrowth and choline acetyltransferase activity in monolayer cultures from chick embryo ciliary ganglia. Brain Res. 1979 Sep 7;173(1):29–45. doi: 10.1016/0006-8993(79)91093-x. [DOI] [PubMed] [Google Scholar]
  32. Zurawski S. M., Zurawski G. Receptor antagonist and selective agonist derivatives of mouse interleukin-2. EMBO J. 1992 Nov;11(11):3905–3910. doi: 10.1002/j.1460-2075.1992.tb05483.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  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. 1992 Jan 17;255(5042):306–312. doi: 10.1126/science.1549776. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES