title: Conformational flexibility tunes the propensity of transthyretin to form fibrils through non-native intermediate states.
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.
authors.affiliation: Structural Biology and Bioinformatics division CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, West Bengal, 700032 (India) https://sites.google.com/site/mukherjeelab/
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Das
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Mall
authors.forename: Aritra
authors.initials: A
authors.lastname: Bej
authors.forename: Sujoy
authors.initials: S
authors.lastname: Mukherjee
mesh_terms: D000682:Amyloid / Q000138:chemical synthesis* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011228:Prealbumin / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D011228:Prealbumin
keywords: Amyloids; NMR spectroscopy; misfolding intermediates; protein folding; transthyretin