Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.

ABSTRACT: A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Our results indicate that W60G low aggregation propensity can be explained, beyond its higher stability, by an increased average protection of the aggregation-prone residues at its surface. To validate these findings, we designed β2m variants that alter the aggregation-prone expose

SUBMITTER: Camilloni C 

PROVIDER: S-EPMC4858664 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature