The molecular interaction of 4'-iodo-4'-deoxydoxorubicin with Leu-55Pro transthyretin 'amyloid-like' oligomer leading to disaggregation.
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.
Sebastião
M P
MP
Molecular Structure Unit, Instituto de Biologia Molecular e Celular, Rua do Campo Alegre, no. 823, 4150 Porto, Portugal.
Merlini
G
G
Saraiva
M J
MJ
Damas
A M
AM
D019943:Amino Acid Substitution / Q000235:genetics*; D000686:Amyloidosis / Q000378:metabolism*; D052160:Benzothiazoles; D003460:Crystallization; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007455:Iodine / Q000378:metabolism; D007930:Leucine / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism; D014961:X-Ray Diffraction
D052160:Benzothiazoles; D011228:Prealbumin; D013844:Thiazoles; C009462:thioflavin T; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin; D007455:Iodine; D011392:Proline; D007930:Leucine