Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The antisense homology box: A new motif within proteins that encodes biologically active peptides

Nature Medicine volume 1, pages 894–901 (1995)Cite this article

Abstract

Amphiphilic peptides approximately fifteen amino acids in length and their corresponding antisense peptides exist within protein molecules. These regions (termed antisense homology boxes) are separated by approximately fifty amino acids. Because many sense–antisense peptide pairs have been reported to recognize and bind to each other, antisense homology boxes may be involved in folding, chaperoning and oligomer formation of proteins. The antisense homology box–derived peptide CALSVDRYRAVASW, a fragment of human endothelin A receptor, proved to be a specific inhibitor of endothelin peptide (ET–1) in a smooth muscle relaxation assay. The peptide was able to block endotoxin–induced shock in rats as well. Our finding of endothelin receptor inhibitor among antisense homology box–derived peptides indicates that searching proteins for this new motif may be useful in finding biologically active peptides.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Blalock, J.E. & Smith, E.M. Hydropathic anti-complementarity of amino acids based on the genetic code. Biochem. Biophys Res. Commun. 121, 203–207 (1984).

    Article  CAS  Google Scholar 

  2. Blalock, J.E. Complementarity of peptides specified by ‘sense’ and ‘antisense’ strands of DNA. Trends Biotech. 6, 140–144 (1991).

    Google Scholar 

  3. Trospha, A., Kizer, J.S. & Chaiken, I.M. Making sense from antisense: A review of experimental data and developing ideas on sense-antisense peptide recognition. J. Molec. Recognition 5, 43–54 (1992).

    Article  Google Scholar 

  4. Eberle, A.N. & Huber, M.J. Antisense peptides: Tools for receptor isolation? Lack of antisense MSH and ACTH to interact with their sense peptides and induce receptor-specific antibodies. Receptor Res. 11, 13–43 (1991).

    Article  CAS  Google Scholar 

  5. Rassmundsen, U.B. & Hesh, R.-D. Antisense peptides: the parathyroid hormone as an experimental example and a critical theoretical view. Biochem. biophys. Res. Commun. 149, 930–938 (1987).

    Article  Google Scholar 

  6. Goldstein, A. & Brutlag, D.L. Is there a relationship between DNA sequences encoding peptide ligands and their receptors? Proc. natn. Acad. Sci. U.S.A. 86, 42–45 (1989).

    Article  CAS  Google Scholar 

  7. Guillemette, G., Boulay, G., Gagnon, S., Bosse, R. & Escher, E. The peptide encoded by angiotensin II complementary RNA does not interfere with angiotensin II action. Biochem. J. 261, 309 (1989).

    Article  CAS  Google Scholar 

  8. de Gasparo, M., Whitebread, S., Einsle, K. & Heusse, C. Are the antibodies to a peptide complementary to angiotensin II useful to isolate angiotensin II receptor? Biochem. J. 261, 310–311 (1989).

    Article  CAS  Google Scholar 

  9. Arai, H., Hori, S., Aramori, I., Ohkubo, H. & Nakanishi, S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348, 730–732 (1990).

    Article  CAS  Google Scholar 

  10. Sakurai, T. et al. Cloning of a cDNA encoding a non-isopeptide selective subtype of the endothelin receptor. Nature 348, 732–735 (1990).

    Article  CAS  Google Scholar 

  11. Clozel, M. et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 365, 759–761 (1993).

    Article  CAS  Google Scholar 

  12. Kon, V. & Awazu, M. Endothelin and cyclosporine nephrotoxicity. Ren. Fail. 14, 345–350 (1992).

    Article  CAS  Google Scholar 

  13. Sokolovsky, M. Endothelins and sarafotoxins: receptor heterogeneity. Int. J. Biochem. 26, 335–340 (1994).

    Article  CAS  Google Scholar 

  14. Moffat, A.S.V. Making sense of antisense. Science 253, 510–511 (1991).

    Article  CAS  Google Scholar 

  15. Draper, K. Self-complementary regions in human albumin mRNA encode important structural regions within the human albumin protein. Biochem. biophys. Res. Commun. 163, 466–470 (1989).

    Article  CAS  Google Scholar 

  16. Bass, B.L. & Weintraub, H. A developmentallly regulated activity that unwinds RNA duplexes. Cell 48, 607–613 (1987).

    Article  CAS  Google Scholar 

  17. Melton, D.A. & Rebagliatti, M.R. Antisense RNA injection in fertilized frog eggs reveals an RNA duplex unwinding activity. Cell 48, 599–605 (1987).

    Article  Google Scholar 

  18. Zull, J.E., Taylor, R.C., Michaelis, G.S. & Rushforth, N.B. Nucleic acid sequences coding for internal antisense peptides: Are there implications for protein folding and evolution? Nucleic Acids Res. 22, 3373–3380 (1994).

    Article  CAS  Google Scholar 

  19. Siegel, S. & Castellan, J.N. Nonparametric Statistics for the Behavioral Sciences, 2nd edn, 40 (McGraw-Hill, New York, 1988).

    Google Scholar 

  20. Fassina, G., Consonni, R., Zetta, L. & Cassani, G. Design of hydropathically complementary peptides for human big endothelin affinity purification. Int. J. Peptide Prot. Res. 39, 540–548 (1992).

    Article  CAS  Google Scholar 

  21. Fassina, G., Thorgeirson, S.S. & Omichinski, J.G. Sequence directed design of recognition peptides. in Methods in Protein Sequence Analysis (ed. Wittman-Liebold, B.) 431–438 (Springer, Berlin, 1989).

    Chapter  Google Scholar 

  22. Fassina, G., Roller, P.P. & Olson, A.D., Thorgeirson, S.S. & Omichinski, J.G. Recognition properties of peptides hydropathically complementary to residues 356-375 of the c-Raf protein. J. biol. Chem. 264, 11252–11257 (1989).

    CAS  PubMed  Google Scholar 

  23. Chou, P.Y. & Fasman, G.D. Conformational parameters for amino acids in helical, beta-sheet and random coil regions calculated from proteins. Biochemistiy 13, 211–221 (1974).

    Article  CAS  Google Scholar 

  24. Bost, K.L., Smith, E.M. & Blalock, J.E. Similarity between the corticotropin (ACTH) receptor and a peptide encoded by an RNA that is complementary to ACTH mRNA. Proc. natn. Acad. Sci. U.S.A. 82, 1372–1375 (1985)

    Article  CAS  Google Scholar 

  25. Kaiser, E.T. & Kezdi, F.J. Secondary structures of proteins and peptides in am-phiphilic environments (a review). Proc. natn. Acad. Sci. U.S.A. 80, 1137–1143 (1983).

    Article  CAS  Google Scholar 

  26. Markus, G., Tritsch, G.L. & Parthasarathy, R. A model for hydropathy-based peptide interaction. Arch. Biochem. Biophys. 272, 433–439 (1989).

    Article  CAS  Google Scholar 

  27. Seckler, R. & Jenicke, R. Protein folding and refolding. FASEB J. 6, 2545–2552 (1992).

    Article  CAS  Google Scholar 

  28. Frerie, E. & Murphy, K.P. Molecular basis of co-operativity in protein folding. J. molec. Biol. 222, 687–698 (1991).

    Article  Google Scholar 

  29. Zull, J.E. & Smith, S.W. Is genetic code redundancy related to retention of structural information in both DNA strands? Trends biochem. Sci. 15, 257–261 (1990).

    Article  CAS  Google Scholar 

  30. Heyl, D.L. et al. Truncated analogues of endothelin and sarafotoxin are selective for the ETB receptor subtype. Pept. Res. 6, 238–241 (1993).

    CAS  PubMed  Google Scholar 

  31. Panek, R.L. et al. Endothelin and structurally related analogs distinguish between endothelin receptor subtypes. Biochem. biophys. Res. Commun., 183, 566–571 (1992).

    Article  CAS  Google Scholar 

  32. Haynes, W.G., Davenport, A.P. & Webb, D.J., Progress in pharmacology and physiology. Trends Pharmac. Sci. 14, 225–228 (1993).

    Article  CAS  Google Scholar 

  33. Seo, B., Oemar, B.S., Siebenmann, R., Segeser, V.L. & Lüscher, T.F., ETa and ETb receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89, 1203–1208 (1994).

    Article  CAS  Google Scholar 

  34. Maemura, K., Kurihara, H., Morita, T., Oh-hashi, Y. & Yazaki, Y. Production of endothelin-1 in vascular endothelial cells is regulated by factors associated with vascular injury. Gerontology 38 (suppl. 1), 29–35 (1992).

    Article  CAS  Google Scholar 

  35. Sakamoto, A. et al. Distinct subdomains of human endothelin receptors determine their selectivity to endothelin A-selective antagonist and endothelin B-selective agonists. J. biol. Chem. 268, 8547–8553 (1993).

    CAS  Google Scholar 

  36. Clarke, B.L. & Blalock, J.E. Steroidogenic activity of a peptide specified by the reversed sequence of corticotropin mRNA. Proc. natn. Acad. Sci. U.S.A. 87, 9708–9711 (1990).

    Article  CAS  Google Scholar 

  37. Araga, S., LeBouf, R.D. & Blalock, J.E. Prevention of experimental myasthenia gravis by manipulation of the immune network with a complementary peptide for the acetylcholine receptor. Proc. natn. Acad. Sci. U.S.A. 90, 8747–8751 (1993).

    Article  CAS  Google Scholar 

  38. Elton, T.S., Dion, L.D., Bost, K.L., Oparil, S. & Blalock, J.E. Purification of an angiotensin II binding protein by using antibodies to a peptide encoded by angiotensin II complementary RNA. Proc. natn. Acad. Sci. U.S.A. 85, 2518–2522 (1988).

    Article  CAS  Google Scholar 

  39. Soffer, R.L. et al. Binding of a novel peptide to the angiotensin II. receptor. Proc. natn. Acad. Sci. U.S.A. 84, 9219–9222 (1987).

    Article  CAS  Google Scholar 

  40. Moore, G.J., Ganter, R.C. & Franklin, K.J. Angiotensin antipeptides: a (−) messenger RNA complementary to human angiotensin II (+) messenger RNA encodes an angiotensin receptor antagonist. Biochem. biophys. Res. Commun. 160, 1387–1391 (1989).

    Article  CAS  Google Scholar 

  41. Johnson, H.M. & Torres, B.A. A novel arginin vasopressin-binding peptide that blocks arginin vasopressin modulation of immune function. J. Immun. 141, 2420–2423 (1988).

    CAS  PubMed  Google Scholar 

  42. Lu, F.X., Aiyar, N. & Chaiken, I. Affinity capture of [Arg8] vasopressin-receptor complex using immobilized antisense peptide. Proc. natn. Acad. Sci. U.S.A. 88, 3642–3646 (1991).

    Article  CAS  Google Scholar 

  43. Chaiken, I., Fassina, G. & Shai, Y. in Protein Recognition of Immobilized Ligands (ed. Hutchens, W.) 257–268 (Liss, New York, 1989).

    Google Scholar 

  44. Shahabi, N.A., Bost, K.L., Madhok, T.C. & Sharp, B.E.M. Characterization of antisera to the naloxon insensitive receptor for beta endorphin on U937 cells generated by using the complementary peptide strategy. J. Pharmac. exp. Ther. 263, 876–883 (1992).

    CAS  Google Scholar 

  45. Zamai, M. & Caiolfa, V.R. Sequence-directed recognition peptides: inhibition of endothelin generation via a substrate depletion mechanism. Biochem. biophys. Acta 1202, 337–340 (1994).

    Google Scholar 

  46. Fassina, G., Germani, S. & Cassani, G. Synthesis of a peptide ligand for bradikinin affinity purification. in Peptides 92 (eds Schneider, C.H. & Eberle, A.N.) 22nd Eur. Peptide Soc. Meeting 1992).

    Google Scholar 

  47. Dillon, J.D., Woods, W.T., Guarchello, V., LeBoeuf, R.D. & Blalock, E. A peptide mimetic of calcium. Proc. natn. Acad. Sci. U.S.A. 88, 9726–9729 (1991).

    Article  CAS  Google Scholar 

  48. Fassina, G., Roller, P.P., Olson, A.D., Thorgeirson, S.S. & Omichinski, J.G. Recognition properties of peptides hydropathically complementary to residues 356-375 of the c-Raf protein. J. biol. Chem. 264, 11252–11257 (1989).

    CAS  PubMed  Google Scholar 

  49. Ghiso, J., Saball, E., Leoni, J., Rostagno, A. & Frangione, B. Binding of cystatin C to C4: the importance of sense–antisense peptides in their interaction. Proc. natn. Acad. Sci. U.S.A. 87, 1288–1291 (1990).

    Article  CAS  Google Scholar 

  50. Nagy, G.M. & Frawley, L.S. A peptide compelementary to a predicted binding region of rat pituitary D2 receptor acts as a dopamine antagonist. 73rd Annu. Meeting, Endocrine Society, Abst. 716, 209 (Endocrine Soc, Bethesda, Maryland, 1991).

  51. Carr, D.J.J., Blalock, J.E. & Bost, K.L. Monoclonal antibody against a peptide specified by [Met]-enkephalin complementary RNA recognizes the delta-class opioid receptor. Immun. Lett. 20, 181–186 (1989).

    Article  CAS  Google Scholar 

  52. Bost, K.L., Smith, E.M. & Blalock, E. Regions of complementarity between the messenger RNAs for epidermal growth factor, transferrin, interleukin-2 and their respective receptors. Biochem. biophys. Res. Commun. 128, 1373–1380 (1985).

    Article  CAS  Google Scholar 

  53. Pasqualini, R., Chamone, D.F. & Brentani, R.R. Determination of the putative binding site for fibronectin on platelet glycoprotein IIb-IIIa complex through a hydropathic complementarity approach. J. biol. Chem. 264, 14566–14570 (1989).

    CAS  PubMed  Google Scholar 

  54. Gartner, K., Loudon, R. & Taylor, R. The peptides APLHK, EHIPA, GSPL, are hydropathically equivalent peptide mimics of a fibrinogen binding domain of glycoprotein IIb/IIIa. Biochem. biophys. Res. Commun. 180, 1446–1452 (1991).

    Article  CAS  Google Scholar 

  55. Brentani, R.R. et al. Characterization of the cellular receptor of fibronectin through a hydropathic complementary approach. Proc. natn. Acad. Sci. U.S.A. 85, 364–367 (1988).

    Article  CAS  Google Scholar 

  56. Carr, D.J.J., Bost, K.L. & Blalock, J.E. An antibody to a peptide specified by an RNA that is complementary to gamma-endorphin RNA recognizes an opiate receptor. J. Neuroimmun. 12, 329–337 (1986).

    Article  CAS  Google Scholar 

  57. McGuigan, J.E. & Campbell-Thompson, M. Complementary peptide to the car-boxyl-terminal tetrapeptide of gastrin. Gastroenterology 103, 749–758 (1992).

    Article  CAS  Google Scholar 

  58. Grosvenor, C.E. & Balint, K. (1989) US patent 4833166.

  59. Eberle, A.N., Drodz, R., Baumann, J.B. & Bost, J.G. Receptor-specific antibodies with “antisense” peptides? Pept. Res. 2, 213–220 (1989).

    CAS  PubMed  Google Scholar 

  60. Bost, K.L. & Blalock, J.E. Production of anti-idiotypic antibodies by immunization with a pair of complementary peptides. J. molec. Recognit. 1, 179–83 (1989).

    Article  CAS  Google Scholar 

  61. Whitacker, J.N., Sparks, B.E., Walker, D.P., Goodin, R. & Benveniste, E.N. Monoclonal iatiotypic and antiidiotypic antibodies produced by immunization with peptides specified by a region of human myelin basic protein mRNA and its complement. J. Neuroimmunol. 22, 157–166 (1989).

    Article  Google Scholar 

  62. Knutson, V.P. Insulin binding peptide. J. biol. Chem. 263, 14146–14151 (1988).

    CAS  PubMed  Google Scholar 

  63. Scapol, L., Rappuoli, P. & Viscomi, G.C. Purification of recombinant human in-terferon beta by immobilized antisense peptide strategy. J. Chromatogr. 600, 235–242 (1992).

    Article  CAS  Google Scholar 

  64. Fassina, G. & Cassini, G. Design and recognition properties of a hydropathically complementary peptide to human interleukin 1 beta. Biochem J. 282, 773–779 (1992).

    Article  CAS  Google Scholar 

  65. Weigent, D.A. et al. The HTLV III envelope protein contains a hexapeptide homologous to a region of interleukin-2 that binds to the interleukin-2 receptor. Biochem. biophys. Res. Commun. 139, 367–374 (1986).

    Article  CAS  Google Scholar 

  66. Castronovo, V., Taraboletti, G. & Sobel, M. Laminin receptor complementary-DNA deduced synthetic peptide inhibits cancer cell attachment to endothelium. Cancer Res. 51, 5672–5678 (1991).

    CAS  PubMed  Google Scholar 

  67. Mulchahey, J.J., Neill, J.D., Dion, J.E., Bost, K.L. & Blalock, J.E. Antibodies to the binding site of the receptor for luteinizing hormone-releasing hormone (LHRH): Generation with synthetic decapeptide encoded by an RNA complementary to LHRH mRNA. Proc. natn. Acad. Sci. U.S.A. 83, 9714–971 (1986).

    Article  CAS  Google Scholar 

  68. Al-Obeidi, F.A. et al. Antisense peptide of melanocyte-stimulating hormone (MSH): Surprising results. in Peptides 89 (eds Rivier, J.E. & Marshall, G.R.) 530–532 (1989).

    Google Scholar 

  69. Zhou, S.R. & Whitacker, J.N. An idiotype shared by monoclonal antibodies to different peptides of human myelin basic protein. J. Immun. 150, 1629–1642 (1993).

    CAS  PubMed  Google Scholar 

  70. Radding, W. et al. A novel peptide blocks canine cardiac ganglia and inhibits the nicotinic receptor of PC-12 cells. J. Autonom. Nerv. Syst. 40, 161–170 (1992).

    Article  CAS  Google Scholar 

  71. Bajpai, A., Hooper, H.K. & Ebner, K. Interactions of antisense peptides with ovine prolactin. Biochem. biophys. Res. Commun. 180, 1312–1317 (1991).

    Article  CAS  Google Scholar 

  72. Carr, D.D.J. et al. Immunoaffinity purified opiate receptor specifically binds the delta-class opiate receptor ligand, cis(+)-3-methylfenanylisothyocianate. FEBBS Lett. 224, 272–276 (1987).

    Article  CAS  Google Scholar 

  73. Shai, Y., Brunck, T.K. & Chaiken, I.M. Antisense peptide recognition of sense peptides: Sequence simplification and evaluation of forces underlying the interaction. Biochemistry 28, 8804–8811 (1989).

    Article  CAS  Google Scholar 

  74. Campbell-Thompson, M. & McGuigan, J.E. Canine parietal cell binding by antibodies to the complementary peptide of somatostatin. Am. J. Med. Sci. 305, 365–373 (1993).

    Article  CAS  Google Scholar 

  75. Bret-Dibat, J.L. et al. Antipeptide antibodies that recognize a substance P-binding site in mammalian tissues: a biochemical and immunochemical study. J. Neurochem. 63, 333–343 (1994).

    Article  CAS  Google Scholar 

  76. Kang, Ch-Y., Brunck, T.K., Kieber-Emmons, T., Blalock, J.E. & Kohler, H. Inhibition of self-binding antibodies (autoantibodies) by Vh-derived peptide. Science 240, 1034–1036 (1988).

    Article  CAS  Google Scholar 

  77. Borovsky, D., Powell, C.A., Nayar, J.K. & Hayes, T.K. Characterization and localization of mosquito-gut receptors for trypsin modulating oostatic factor using a complementary peptide and immunocytochemistry. FASEB J. 8, 350–355 (1994).

    Article  CAS  Google Scholar 

  78. Kelly, J.M. et al. Vasopressin antisense peptide interactions with the V1 receptor. Peptides 11, 857–862 (1990).

    Article  CAS  Google Scholar 

  79. Gartner, K. & Taylor, D.B. The peptide glu-his-ile-pro-ala binds to fibrinogen and inhibits platelet aggregation and adhesion to fibrinogen and vitronectin. Proc. Soc. exp. Biol. Med. 198, 649–655 (1991).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Choju Medical Institute, Noyori Fukushimura Hospital, Noyori-cho, Toyohashi, 441, Japan

    Lajos Baranyi & William Campbell

  2. Department of Molecular Biology, Nagoya City University School of Medicine, Mizuho-cho, Nagoya, 467, Japan

    Lajos Baranyi, William Campbell, Kunihiro Ohshima & Hidechika Okada

  3. Department of Pharmacology, Nagoya City University School of Medicine, Mizuho-cho, Nagoya, 467, Japan

    Seigo Fujimoto

  4. Institute of Experimental Surgery, Szent-Györgyi Albert Medical University, H-6723, Szeged, Hungary

    MiháLy Boros

Authors
  1. Lajos Baranyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kunihiro Ohshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seigo Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. MiháLy Boros
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hidechika Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baranyi, L., Campbell, W., Ohshima, K. et al. The antisense homology box: A new motif within proteins that encodes biologically active peptides. Nat Med 1, 894–901 (1995). https://doi.org/10.1038/nm0995-894

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0995-894

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing