Transthyretin variants with improved inhibition of β-amyloid aggregation.

ABSTRACT: Aggregation of β-amyloid (Aβ) is widely believed to cause neuronal dysfunction in Alzheimer's disease. Transthyretin (TTR) binds to Aβ and inhibits its aggregation and neurotoxicity. TTR is a homotetrameric protein, with each monomer containing a short α-helix and two anti-parallel β-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 Aβ aggregation than wild-type (WT) TTR, although N98A and WT bound Aβ equally. The N98A mutation is located on a flexible loop distant from the putative Aβ-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 le

SUBMITTER: Mangrolia P 

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

REPOSITORIES: biostudies-literature