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) va riant has revealed an oligomer structure that may represent a putative amyl oid protofibril [Sebastiao, Saraiva and Damas (1998) J. Biol. Chem. 273, 24 715-24722]. Here we report biochemical evidence that corroborates the isola tion of an intermediate structure, an 'amyloid-like' oligomer, which is mos t probably present in the biochemical pathway that leads to amyloid deposit ion and that was isolated by the crystallization of the Leu-55Pro TTR varia nt. 4'-Iodo-4'-deoxydoxorubicin (IDOX) is a compound that interacts with am yloid fibrils of various compositions and it has been reported to reduce th e 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, w e observed that the monoclinic Leu-55Pro TTR crystals, soaked with IDOX, un dergo rapid dissociation. Moreover, under the same conditions, the orthorho mbic wild-type TTR crystals are quite stable. This is explained by the diff erent TTR conformations isolated upon crystallization of the two proteins; while the Leu-55Pro TTR exhibits the necessary conformation for IDOX bindin g, 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 locate d between the two beta-sheets of the Leu-55Pro TTR monomer with the IDOX ar omatic-moiety long axis nearly perpendicular to the direction of the beta-s heets.