Human-murine transthyretin heterotetramers are kinetically stable and non-amyloidogenic. A lesson in the generation of transgenic models of diseases involving oligomeric proteins.

摘要: 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 extracellular deposition amorphous aggregates amyloid fibrils. Mice transgenic for few copies amyloid-prone variants, including aggressive L55P mutant, failed develop deposits. Silencing murine gene presence resulted enhanced tissue deposition. To test hypothesis that interacted with preventing required amyloidogenesis, we produced recombinant human/murine heterotetramers compared their structures biophysical properties transthyretin. We found no significant differences between crystal homotetramers. Murine is not amyloidogenic because native homotetramer kinetically stable under physiologic conditions cannot dissociate into partially unfolded monomers, misfolding precursor. Heterotetramers composed subunits are also stable. These observations explain lack transgenics carrying a low copy number genes. incorporation mouse tetramers otherwise imposes kinetic stability, subsequent amyloidogenesis.