Transthyretin variants with improved inhibition of ?-amyloid aggregation.

ABSTRACT: Aggregation of ?-amyloid (A?) is widely believed to cause neuronal dysfunction in Alzheimer's disease. Transthyretin (TTR) binds to A? and inhibits its aggregation and neurotoxicity. TTR is a homotetrameric protein, with each monomer containing a short ?-helix and two anti-parallel ?-sheets. Dimers pack into tetramers to form a hydrophobic cavity. Here we report the discovery of a TTR mutant, N98A, that was more effective at inhibiting A? aggregation than wild-type (WT) TTR, although N98A and WT bound A? equally. The N98A mutation is located on a flexible loop distant from the putative A?-binding sites and does not alter secondary and tertiary structures nor prevent correct assembly into tetramers. Under non-physiological conditions, N98A tetramers were kinetically and thermodynamically less stable than WT, suggesting a difference in the tetramer folded structure. In vivo, the lone cysteine in TTR is frequently modified by S-cysteinylation or S-sulfonation. Like the N98A mutation, S-cysteinylation of TTR modestly decreased tetramer stability and increased TTR's effectiveness at inhibiting A? aggregation. Collectively, these data indicate that a subtle change in TTR tetramer structure measurably increases TTR's ability to inhibit A? aggregation.

SUBMITTER: Mangrolia P 

PROVIDER: S-EPMC4867095 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature