2qpf

From Proteopedia

Revision as of 15:28, 6 February 2008

Crystal Structure of Mouse Transthyretin

Overview

The transthyretin amyloidoses appear to be caused by rate-limiting, tetramer dissociation and partial monomer unfolding of the human serum, protein transthyretin, resulting in aggregation and extracellular, deposition of amorphous aggregates and amyloid fibrils. Mice transgenic, for few copies of amyloid-prone human transthyretin variants, including, the aggressive Leu55Pro mutant, failed to develop deposits. Silencing the, murine transthyretin gene in the presence of the Leu55Pro human gene, resulted in enhanced tissue deposition. To test the hypothesis that the, murine protein interacted with human transthyretin, preventing the, dissociation and partial unfolding required for amyloidogenesis, we, produced recombinant murine transthyretin and human/murine transthyretin, heterotetramers and compared their structures and biophysical properties, to recombinant human transthyretin. We found no significant differences, between the crystal structures of murine and human homotetramers. Murine, transthyretin is not amyloidogenic because the native homotetramer is, kinetically stable under physiologic conditions and cannot dissociate into, partially unfolded monomers, the misfolding and aggregation precursor., Heterotetramers composed of murine and human subunits are also kinetically, stable. These observations explain the lack of TTR deposition in, transgenics carrying a low copy number of human transthyretin genes. The, incorporation of mouse subunits into tetramers otherwise composed of human, amyloid-prone transthyretin subunits imposes kinetic stability, preventing, dissociation and subsequent amyloidogenesis. The results demonstrate that, interspecies oligomers may have different biophysical characteristics than, the corresponding homo-oligomers and suggest that the elimination of the, endogenous protein might be required to obtain the desired disease, phenotype in transgenic models.

About this Structure

2QPF is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

Reference

Human-murine transthyretin heterotetramers are kinetically stable and non-amyloidogenic: A lesson in the generation of transgenic models of diseases involving oligomeric proteins., Reixach N, Foss TR, Santelli E, Pascual J, Kelly JW, Buxbaum JN, J Biol Chem. 2007 Nov 15;. PMID:18006495

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