All-Atom Simulations Reveal How Single-Point Mutations Promote Serpin Misfolding.

ABSTRACT: Protein misfolding is implicated in many diseases, including serpinopathies. For the canonical inhibitory serpin ?1-antitrypsin, mutations can result in protein deficiencies leading to lung disease, and misfolded mutants can accumulate in hepatocytes, leading to liver disease. Using all-atom simulations based on the recently developed bias functional algorithm, we elucidate how wild-type ?1-antitrypsin folds and how the disease-associated S (Glu264Val) and Z (Glu342Lys) mutations lead to misfolding. The deleterious Z mutation disrupts folding at an early stage, whereas the relatively benign S mutant shows late-stage minor misfolding. A number of suppressor mutations ameliorate the effects of the Z mutation, and simulations on these mutants help to elucidate the relative roles of steric clashes and electrostatic interactions in Z misfolding. These results demonstrate a striking correlation between atomistic events and disease severity and shine light on the mechanisms driving chains away from their correct folding routes.

SUBMITTER: Wang F 

PROVIDER: S-EPMC5961751 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature