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Quaternary structure, aggregation and cytotoxicity of transthyretin
Mineyuki Mizuguchi1, Takeshi Yokoyama, Yuko Nabeshima
1Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan. mineyuki@pha.u-toyama.ac.jp
Abstract:
Transthyretin (TTR) with a Ser112-to-Ile mutation is known to cause amyloidosis with severe cardiomyopathy. We investigated the quaternary structure, aggregation and cytotoxicity of the S112I variant. This variant exists as a dimer at physiological pH, self-assembles into spherical aggregates and induces cell death in human neuroblastoma IMR-32 cells. In addition, we determined the neutron crystal structure of TTR at 2.0 Å resolution. The neutron structure revealed that the hydrogen-bond network involving His88 is important for the stabilization of the dimer-dimer and monomer-monomer interfaces.
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