Conformational flexibility tunes the propensity of transthyretin to form fibrils through non-native intermediate states
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Conformational flexibility tunes the propensity of transthyretin to form fibrils through non-native intermediate states
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| Creator |
Das, Jitendra K
Mall, Shyam S Bej, Aritra Mukherjee, Sujoy |
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| Subject |
Structural Biology & Bioinformatics
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| Description |
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 wildtype 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.
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| Publisher |
John Wiley & Sons
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| Date |
2014
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2134/1/ANGEWANDTE_CHEMIE%2DINTERNATIONAL_EDITION___53_(_47)__12781%2D12784_;2014.pdf
Das, Jitendra K and Mall, Shyam S and Bej, Aritra and Mukherjee, Sujoy (2014) Conformational flexibility tunes the propensity of transthyretin to form fibrils through non-native intermediate states. Angewandte Chemie, 53 (47). pp. 12781-12784. ISSN 0044-8249 |
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| Relation |
http://dx.doi.org/10.1002/anie.201407323.
http://www.eprints.iicb.res.in/2134/ |
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