Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2000 Oct 1;351(Pt 1):273–279. doi: 10.1042/0264-6021:3510273

The molecular interaction of 4'-iodo-4'-deoxydoxorubicin with Leu-55Pro transthyretin 'amyloid-like' oligomer leading to disaggregation.

M P Sebastião 1, G Merlini 1, M J Saraiva 1, A M Damas 1
PMCID: PMC1221359  PMID: 10998371

Abstract

The crystal structure of the amyloidogenic Leu-55Pro transthyretin (TTR) variant has revealed an oligomer structure that may represent a putative amyloid protofibril [Sebastião, Saraiva and Damas (1998) J. Biol. Chem. 273, 24715-24722]. Here we report biochemical evidence that corroborates the isolation of an intermediate structure, an 'amyloid-like' oligomer, which is most probably present in the biochemical pathway that leads to amyloid deposition and that was isolated by the crystallization of the Leu-55Pro TTR variant. 4'-Iodo-4'-deoxydoxorubicin (IDOX) is a compound that interacts with amyloid fibrils of various compositions and it has been reported to reduce the amyloid load in immunoglobulin light chain amyloidosis [Merlini, Ascari, Amboldi, Bellotti, Arbustini, Perfetti, Ferrari, Zorzoli, Marinone, Garini et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 2959-2963]. In this work, we observed that the monoclinic Leu-55Pro TTR crystals, soaked with IDOX, undergo rapid dissociation. Moreover, under the same conditions, the orthorhombic wild-type TTR crystals are quite stable. This is explained by the different TTR conformations isolated upon crystallization of the two proteins; while the Leu-55Pro TTR exhibits the necessary conformation for IDOX binding, the same structure is not present in the crystallized wild-type protein. A theoretical model concerning the interaction of Leu-55Pro TTR with IDOX, which is consistent with the dissociation of the amyloid-like oligomer, is presented. In this model the IDOX iodine atom is buried in a pocket located between the two beta-sheets of the Leu-55Pro TTR monomer with the IDOX aromatic-moiety long axis nearly perpendicular to the direction of the beta-sheets.

Full Text

The Full Text of this article is available as a PDF (273.5 KB).

Selected References

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

  1. Almeida M. R., Damas A. M., Lans M. C., Brouwer A., Saraiva M. J. Thyroxine binding to transthyretin Met 119. Comparative studies of different heterozygotic carriers and structural analysis. Endocrine. 1997 Jun;6(3):309–315. doi: 10.1007/BF02820508. [DOI] [PubMed] [Google Scholar]
  2. Barbieri B., Giuliani F. C., Bordoni T., Casazza A. M., Geroni C., Bellini O., Suarato A., Gioia B., Penco S., Arcamone F. Chemical and biological characterization of 4'-iodo-4'-deoxydoxorubicin. Cancer Res. 1987 Aug 1;47(15):4001–4006. [PubMed] [Google Scholar]
  3. Blake C. C., Geisow M. J., Oatley S. J., Rérat B., Rérat C. Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A. J Mol Biol. 1978 May 25;121(3):339–356. doi: 10.1016/0022-2836(78)90368-6. [DOI] [PubMed] [Google Scholar]
  4. Bonifácio M. J., Sakaki Y., Saraiva M. J. 'In vitro' amyloid fibril formation from transthyretin: the influence of ions and the amyloidogenicity of TTR variants. Biochim Biophys Acta. 1996 May 24;1316(1):35–42. doi: 10.1016/0925-4439(96)00014-2. [DOI] [PubMed] [Google Scholar]
  5. Danesi R., Marchetti A., Bernardini N., La Rocca R. V., Bevilacqua G., Del Tacca M. Cardiac toxicity and antitumor activity of 4'-deoxy-4'-iodo-doxorubicinol. Cancer Chemother Pharmacol. 1990;26(6):403–408. doi: 10.1007/BF02994089. [DOI] [PubMed] [Google Scholar]
  6. Gianni L., Bellotti V., Gianni A. M., Merlini G. New drug therapy of amyloidoses: resorption of AL-type deposits with 4'-iodo-4'-deoxydoxorubicin. Blood. 1995 Aug 1;86(3):855–861. [PubMed] [Google Scholar]
  7. Hamilton J. A., Steinrauf L. K., Braden B. C., Liepnieks J., Benson M. D., Holmgren G., Sandgren O., Steen L. The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution. J Biol Chem. 1993 Feb 5;268(4):2416–2424. [PubMed] [Google Scholar]
  8. Howlett D. R., George A. R., Owen D. E., Ward R. V., Markwell R. E. Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer beta-amyloid fibril formation. Biochem J. 1999 Oct 15;343(Pt 2):419–423. [PMC free article] [PubMed] [Google Scholar]
  9. Jacobson D. R., McFarlin D. E., Kane I., Buxbaum J. N. Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. Hum Genet. 1992 May;89(3):353–356. doi: 10.1007/BF00220559. [DOI] [PubMed] [Google Scholar]
  10. Katchalski-Katzir E., Shariv I., Eisenstein M., Friesem A. A., Aflalo C., Vakser I. A. Molecular surface recognition: determination of geometric fit between proteins and their ligands by correlation techniques. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2195–2199. doi: 10.1073/pnas.89.6.2195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kretsinger R. H., Watson H. C., Kendrew J. C. Binding of mercuri-iodide and related ions to crystals of sperm whale metmyoglobin. J Mol Biol. 1968 Jan 28;31(2):305–314. doi: 10.1016/0022-2836(68)90446-4. [DOI] [PubMed] [Google Scholar]
  12. Lashuel H. A., Wurth C., Woo L., Kelly J. W. The most pathogenic transthyretin variant, L55P, forms amyloid fibrils under acidic conditions and protofilaments under physiological conditions. Biochemistry. 1999 Oct 12;38(41):13560–13573. doi: 10.1021/bi991021c. [DOI] [PubMed] [Google Scholar]
  13. LeVine H., 3rd Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 1993 Mar;2(3):404–410. doi: 10.1002/pro.5560020312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McCutchen S. L., Colon W., Kelly J. W. Transthyretin mutation Leu-55-Pro significantly alters tetramer stability and increases amyloidogenicity. Biochemistry. 1993 Nov 16;32(45):12119–12127. doi: 10.1021/bi00096a024. [DOI] [PubMed] [Google Scholar]
  15. Merlini G., Anesi E., Garini P., Perfetti V., Obici L., Ascari E., Lechuga M. H., Capri G., Gianni L. Treatment of AL amyloidosis with 4'-lodo-4'-deoxydoxorubicin: an update. Blood. 1999 Feb 1;93(3):1112–1113. [PubMed] [Google Scholar]
  16. Monaco H. L., Rizzi M., Coda A. Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science. 1995 May 19;268(5213):1039–1041. doi: 10.1126/science.7754382. [DOI] [PubMed] [Google Scholar]
  17. Mross K., Mayer U., Langenbuch T., Hamm K., Burk K., Hossfeld D. Toxicity, pharmacokinetics and metabolism of iododoxorubicin in cancer patients. Eur J Cancer. 1990;26(11-12):1156–1162. doi: 10.1016/0277-5379(90)90276-y. [DOI] [PubMed] [Google Scholar]
  18. Palha J. A., Ballinari D., Amboldi N., Cardoso I., Fernandes R., Bellotti V., Merlini G., Saraiva M. J. 4'-Iodo-4'-deoxydoxorubicin disrupts the fibrillar structure of transthyretin amyloid. Am J Pathol. 2000 Jun;156(6):1919–1925. doi: 10.1016/S0002-9440(10)65065-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Podestà A., Della Torre P., Pinciroli G., Iatropoulos M. J., Brughera M., Mazué G. Evaluation of 4'-iodo-4'-deoxydoxorubicin-induced cardiotoxicity in two experimental rat models. Toxicol Pathol. 1994 Jan-Feb;22(1):68–71. doi: 10.1177/019262339402200109. [DOI] [PubMed] [Google Scholar]
  20. Saraiva M. J., Costa P. P., Goodman D. S. Transthyretin (prealbumin) in familial amyloidotic polyneuropathy: genetic and functional aspects. Adv Neurol. 1988;48:189–200. [PubMed] [Google Scholar]
  21. Saraiva M. J. Transthyretin mutations in health and disease. Hum Mutat. 1995;5(3):191–196. doi: 10.1002/humu.1380050302. [DOI] [PubMed] [Google Scholar]
  22. Sebastião M. P., Saraiva M. J., Damas A. M. The crystal structure of amyloidogenic Leu55 --> Pro transthyretin variant reveals a possible pathway for transthyretin polymerization into amyloid fibrils. J Biol Chem. 1998 Sep 18;273(38):24715–24722. doi: 10.1074/jbc.273.38.24715. [DOI] [PubMed] [Google Scholar]
  23. Sebastião P., Dauter Z., Saraiva M. J., Damas A. M. Crystallization and preliminary X-ray diffraction studies of Leu55Pro variant transthyretin. Acta Crystallogr D Biol Crystallogr. 1996 May 1;52(Pt 3):566–568. doi: 10.1107/S0907444995013965. [DOI] [PubMed] [Google Scholar]
  24. Sobolev V., Wade R. C., Vriend G., Edelman M. Molecular docking using surface complementarity. Proteins. 1996 May;25(1):120–129. doi: 10.1002/(SICI)1097-0134(199605)25:1<120::AID-PROT10>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  25. Tagliavini F., McArthur R. A., Canciani B., Giaccone G., Porro M., Bugiani M., Lievens P. M., Bugiani O., Peri E., Dall'Ara P. Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science. 1997 May 16;276(5315):1119–1122. doi: 10.1126/science.276.5315.1119. [DOI] [PubMed] [Google Scholar]
  26. Vakser I. A., Matar O. G., Lam C. F. A systematic study of low-resolution recognition in protein--protein complexes. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8477–8482. doi: 10.1073/pnas.96.15.8477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Villani F., Galimberti M., Comazzi R. Early cardiac toxicity of 4'-iodo-4'-deoxydoxorubicin. Eur J Cancer. 1991;27(12):1601–1604. doi: 10.1016/0277-5379(91)90423-b. [DOI] [PubMed] [Google Scholar]
  28. Villani F., Galimberti M., Lanza E., Rozza A., Favalli L., Poggi P. Evaluation of cardiotoxicity of a new anthracycline derivative: 4'-deoxy-4'-iodo-doxorubicin. Invest New Drugs. 1988 Sep;6(3):173–178. doi: 10.1007/BF00175394. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES