Characterization of the interaction of β-amyloid with transthyretin monomers and tetramers.
β-Amyloid (Aβ) is the main protein component of the amyloid plaques associated with Alzheimer's disease. Transthyretin (TTR) is a homotetramer that circulates in both blood and cerebrospinal fluid. Wild-type (wt) TTR amyloid deposits are linked to senile systemic amyloidosis, a common disease of aging, while several TTR mutants are linked to familial amyloid polyneuropathy. Several recent studies provide support for the hypothesis that these two amyloidogenic proteins interact, and that this interaction is biologically relevant. For example, upregulation of TTR expression in Tg2576 mice was linked to protection from the toxic effects of Aβ deposition [Stein, T. D., and Johnson, J. A. (2002) J. Neurosci. 22, 7380-7388]. We examined the interaction of Aβ with wt TTR as well as two mutants: F87M/L110M, engineered to be a stable monomer, and T119M, a naturally occurring mutant with a tetrameric stability higher than that of the wild type. On the basis of enzyme-linked immunoassays as well as cross-linking experiments, we conclude that Aβ monomers bind more to TTR monomers than to TTR tetramers. The data further suggest that TTR tetramers interact preferably with Aβ aggregates rather than Aβ monomers. Through tandem mass spectrometry analysis of cross-linked TTR-Aβ fragments, we identified the A strand, in the inner β-sheet of TTR, as well as the EF helix, as regions of TTR that are involved with Aβ association. Light scattering and electron microscopy studies demonstrate that the outcome of the TTR-Aβ interaction strongly depends on TTR quaternary structure. While TTR tetramers may modestly enhance aggregation, TTR monomers decidedly arrest Aβ aggregate growth. These data provide important new insights into the nature of TTR-Aβ interactions. Such interactions may regulate TTR-mediated protection against Aβ toxicity.
Du
Jiali
J
Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, Wisconsin 53706, USA.
Murphy
Regina M
RM
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D046911:Macromolecular Substances; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D011228:Prealbumin; D011994:Recombinant Proteins
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