Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics.

ABSTRACT: Native transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at β-strands E and F and EF-loop. The monomer-mo

SUBMITTER: Saldano TE 

PROVIDER: S-EPMC5509292 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature