Secrets of disease-causing amyloids unveiled
doi:10.1038/nindia.2014.171 Published online 17 December 2014
Using spectroscopic analysis and molecular dynamics simulations, researchers have gained new insights into how a thyroxine-carrying protein, transthyretin, forms fibrillar structures known as amyloids1. Amyloids accumulate in different organs and tissues, where they cause a wide range of health problems, including heart enlargement, muscle stiffness, dry eyes and memory loss. The insights will facilitate the prediction of the pathogenic potential of transthyretin and other proteins that cause health problems through forming amyloids.
Gene-directed protein synthesis produces proteins that are linear chains of amino acids. Such proteins can only function correctly when they fold into three-dimensional structures. This folding occurs via transient intermediate structures. But mutations in a gene cause a protein to fold incorrectly so that it forms an intermediate structure that generates amyloids through aggregation. In particular, mutations in the gene that encodes transthyretin cause this protein to fold incorrectly and form amyloid-forming intermediates.
To better understand the process of amyloid formation from transthyretin-derived intermediates, the researchers probed the backbone dynamics of normal transthyretin and four mutant transthyretins by employing nuclear magnetic resonance spectroscopy and molecular dynamics simulations.
The researchers found that the mutant transthyretins formed larger populations of intermediates, which had lower free energies and faster conversion kinetics than the native proteins. These properties may facilitate the aggregation of the mutant-protein-derived intermediates that form amyloids.
“Having a better understanding of the transthyretin aggregation process will help develop molecules that inhibit amyloid formation by stabilizing transthyretin’s structure and neutralizing its toxic intermediates,” says lead researcher Sujoy Mukherjee.
1. Das, J. K. et al. Conformational flexibility tunes the propensity of transthyretin to form fibrils through non-native intermediate states. Angew. Chem. Int. Ed. 53, 12781–12784 (2014) doi: 10.1002/anie.201407323