Premium
Conformational Flexibility Tunes the Propensity of Transthyretin to Form Fibrils Through Non‐Native Intermediate States
Author(s) -
Das Jitendra K.,
Mall Shyam S.,
Bej Aritra,
Mukherjee Sujoy
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201407323
Subject(s) - chemistry , transthyretin , dissociation (chemistry) , fibril , native state , intermediate state , biophysics , population , protein structure , molecular dynamics , stereochemistry , crystallography , computational chemistry , biochemistry , biology , organic chemistry , philosophy , demography , theology , sociology , endocrinology
Abstract The formation of partially unfolded intermediates through conformational excursions out of the native state is the starting point of many diseases involving protein aggregation. Therapeutic strategies often aim to stabilize the native structure and prevent the formation of intermediates that are also cytotoxic in vivo. However, their transient nature and low population makes it difficult to characterize these intermediates. We have probed the backbone dynamics of transthyretin (TTR) over an extended timescale by using NMR spectroscopy and MD simulations. The location and extent of these motions indicates that the backbone flexibility of TTR is a cause of dissociation and destabilization, both of which are responsible for fibril formation. Importantly, approximately 10 % of wild‐type TTR exists in an intermediate state, which increased to up to 28 % for pathogenic TTR mutants, for which the formation of the intermediate state is shown to be energetically more favorable compared to the wild type. This result suggests an important role for the intermediates in TTR amyloidosis.