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2001 | 48 | 4 | 867-875
Article title

Structural basis of negative cooperativity in transthyretin

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A comparison of the AC and BD binding sites of transthyretin (TTR) was made in terms of the interatomic distances between the Cα atoms of equivalent amino acids, measured across the tetramer channel in each binding site. The comparison of the channel diameter for apo TTR from different sources revealed that in the unliganded transthyretin tetramers the distances between the A, D and H β-strands are consistently larger, while the distances between the G β-strands are smaller in one site than in the other. These differences might be described to have a 'wave' character. An analogous analysis performed for transthyretin complexes reveals that the shape of the plot is similar, although the amplitudes of the changes are smaller. The analysis leads us to a model of the changes in the binding sites caused by ligand binding. The sequence of events includes ligand binding in the first site, followed by a slight collapse of this site and concomitant opening of the second site, binding of the second molecule and collapse of the second site. The following opening of the first, already occupied site upon ligand binding in the second site is smaller because of the bridging interactions already formed by the first ligand. This explains the negative cooperativity (NC) effect observed for many ligands in transthyretin.
Physical description
  • Institute of Chemistry, Nicolaus Copernicus University, Toruń, Poland
  • Hauptman-Woodward Medical Research Institute, Inc., Buffalo, U.S.A.
  • Institute of Chemistry, Nicolaus Copernicus University, Toruń, Poland
  • 1. Kelly, J.W. (1997) Amyloid fibril formation and protein misassembly: A structural quest for insights into amyloid and prion diseases. Structure 5, 595-600.
  • 2. Kelly, J.W. & Lansbury, P.T.J. (1994) A chemical approach to elucidate the mechanism of transthyretin and beta-protein amyloid fibril formation. Amyloid 1, 186-205.
  • 3. Klabunde, T., Petrassi, H.M., Oza, V.B., Raman, P., Kelly, J.W. & Sacchetti, J.C. (2000) Rational design of potent human transthyretin amyloid disease inhibitors. Nat. Struct. Biol. 7, 312-321.
  • 4. Blake, C.C.F & Oatley, S.J. (1977) Protein-DNA and protein-hormone interactions in prealbumin: A model of the thyroid hormone nuclear receptor? Nature 268, 115-129.
  • 5. Wojtczak, A., Cody, V., Luft, J.R. & Pangborn, W. (1996) Structures of human transthyretin complexed with thyroxine at 2.0 Å resolution and 3',5'-dinitro-N-acetyl-L-thyronine at 2.2 Å resolution. Acta Crystallogr. D 52, 758-765.
  • 6. Wojtczak, A., Luft, J. R. & Cody, V. (1992) Mechanism of molecular recognition: Structural aspects of 3,3'-diiodo-L-thyronine binding to human serum transthyretin. J. Biol. Chem. 267, 353-357.
  • 7. Wojtczak, A., Luft, J.R. & Cody, V. (1993) Structural aspects of inotropic bipyridine binding: Crystal structure determination to 1.9 Å of the human serum transthyretin-milrinone complex. J. Biol. Chem. 268, 6202-6206.
  • 8. Ciszak, E., Luft, J. & Cody, V. (1992) Crystal structure determination at 2.3-Å resolution of human transthyretin-3',5'-dibromo-2',4,4',6- tetrahydroxyaurone complex. Proc. Natl. Acad. Sci. U.S.A. 89, 6644-6648.
  • 9. Cody, V., Wojtczak, A., Ciszak, E. & Luft, J. (1991) Differences in inhibitor and substrate binding in transthyretin crystal complexes; in Progress in Thyroid Research (Gordon, A., Gross, J. & Hennemann, G., eds.) pp. 793-796, Balkema, Rotterdam.
  • 10. Hamilton, J.A., Steinrauf, L.K., Braden, B.C., Liepniks, J., Benson, M.D., Holmgren, G., Sandgren, O. & Steen, L. (1993) The X-Ray crystal structure refinements of normal human transthyretin and theamyloidogenic Val30Met variant to 1.7 Å resolution. J. Biol. Chem. 268, 2416-2424.
  • 11. Steinrauf, L.K., Hamilton, J.A., Braden, B.C., Murrell, J.R., Benson, M.D., Holmgren, G. Sandgren, O. & Steen, L. (1993) X-Ray crystal structure of the Ala-109-Thr variant of human TTR which produceseuthyroid hyperthyroxinemia. J. Biol. Chem. 268, 2425-2430.
  • 12. Peterson, S.A., Klabunde, T., Lashuel, H.A., Purkey, H., Sacchettini, J.C. & Kelly, J.W. (1998) Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc. Natl. Acad. Sci. U.S.A. 95, 12956-12960.
  • 13. Sunde, M., Richardson, S.J., Chang, L., Petterson, T.M., Schreiber, G. & Blake, C.C.F. (1996) The crystal structure of transthyretin from chicken. Eur. J. Biochem. 236, 491-499.
  • 14. Hornberg, A., Eneqvist, T., Olofsson, A., Lundgren, E. & Sauer-Eriksson, A.E. (2000) A comparative analysis of 23 structures of the amyloidogenic protein transthyretin. J. Mol. Biol. 302, 649-669.
  • 15. Wojtczak, A., Neumann, P. & Cody, V. (2001) Structure of a new polymorphic monoclinic form of human transthyretin at 3 Å resolution reveals a mixed complex between unliganded and T4-bound tetramers of TTR. Acta Crystallogr. D 57, 957-967
  • 16. Wojtczak, A. (1997) Crystal structure of rat transthyretin at 2.5 Å resolution: First report on a unique tetrameric structure. Acta Biochim. Polon. 44, 505-518.
  • 17. Wojtczak, A., Cody, V., Luft, J. & Pangborn, W. (2001) Structure of rat transthyretin (rTTR) complex with thyroxine at 2.5 Å resolution: First non-biased insight into thyroxine binding reveals different hormone orientation in two binding sites. Acta Crystallogr. D57, 1061-1070.
  • 18. Ferguson, R.N., Edeldoch, H., Saroff, H.A. & Robbins, J. (1975) Negative cooperativity in the binding of thyroxine to human serum transthyretin. Biochemistry 14, 282-289.
  • 19. Cheng, S., Pages, R.A., Saroff, H.A., Edelhoch, H. & Robbins, J. (1977) Analysis of thyroid hormone binding to human serum prealbumin by 8-anilinonaphthalene-1-sulfonate fluorescence. Biochemistry 16, 3707-3713.
  • 20. Miroy, G.J., Lai, Z., Lashuel, A., Peterson, S.A., Strang, C. & Kelly, J.W. (1996) Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc. Natl. Acad. Sci. U.S.A. 93, 15051-15056.
  • 21. González, G. & Tapia, G. (1992) Fluorescence study of the thyroxine-dependent conformational changes in human serum transthyretin. FEBS Lett. 297, 253-256.
  • 22. González, G. (1989) Fluorescent derivative of cysteine-10 reveals thyroxine-dependent conformational modifications in human serum prealbumin. Arch. Biochem. Biophys. 271, 200-205.
  • 23. Brünger, A., XPLOR Version 3.1. A System for X-ray Crystallography and NMR. (1992) Yale University Press.
  • 24. Brünger, A.T., Adams, P.D., Clore, G.M., DeLano, W. L., Gros, P., Grosse-Kunstleve, R.W., Jiang, J.-S., Kuszewski, J., Nilges, M., Pannu, N.S., Read, R.J., Rice, L.M., Simonson, T. & Warren, G.L. (1998) Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D54, 905-921.
  • 25. Gosh, M., Meerts, I.A., Cook, A., Bergman, A., Brouwer, A. & Johnson, L.N. (2000) Structure of human transthyretin complexed with bromophenols: A new mode of binding. Acta Crystallogr. D 56, 1085-1092.
  • 26. Wojtczak, A., Neumann, P., Muzioł, T. & Cody, V. (2001) Novel binding mode of tetraiodothyroacetic acid in transthyretin. Acta Crystallogr. D. Submitted.
  • 27. Irace, G. & Edelhoch, H. (1978) Thyroxine-induced conformational changes in prealbumin. Biochemistry 17, 5729-5733.
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Publication order reference
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