Characterization of the interaction of β-amyloid with transthyretin monomers and tetramers.
Characterization of the interaction of β-amyloid with transthyretin monomers and tetramers.
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DOI：
10.1021/bi101280t
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发表时间：
2010-09-28
期刊：
影响因子：
2.9
通讯作者：
Murphy, Regina M.
中科院分区：
文献类型：
--
作者：
Du, Jiali;Murphy, Regina M.
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 transthyretin (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 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 higher tetrameric stability than wildtype. Based on enzyme-linked immunoassays as well as crosslinking experiments, we conclude that Aβ monomers bind more strongly 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 crosslinked 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.
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