Loosening of Side-Chain Packing Associated with Perturbations in Peripheral Dynamics Induced by the D76N Mutation of β₂-Microglobulin Revealed by Pressure-NMR and Molecular Dynamic Simulations.

ABSTRACT: β₂-Microglobulin (β₂m) is the causative protein of dialysis-related amyloidosis, and its D76N variant is less stable and more prone to aggregation. Since their crystal structures are indistinguishable from each other, enhanced amyloidogenicity induced by the mutation may be attributed to changes in the structural dynamics of the molecule. We examined pressure and mutation effects on the β₂m molecule by NMR and MD simulations, and found that the mutation induced the loosening of the inter-sheet packing of β₂m, which is relevant to destabilization and subsequent amyloidogenicity. On the other hand, this loosening was coupled with perturbed dynamics at some peripheral regions. The key result for this conclusion was that both the mutation and pressur

SUBMITTER: Sakurai K 

PROVIDER: S-EPMC6769805 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature