NMR Measurements Reveal the Structural Basis of Transthyretin Destabilization by Pathogenic Mutations.

ABSTRACT: Inherited mutations of transthyretin (TTR) destabilize its structure, leading to aggregation and familial amyloid disease. Although numerous crystal structures of wild-type (WT) and mutant TTRs have been determined, they have failed to yield a comprehensive structural explanation for destabilization by pathogenic mutations. To identify structural and dynamic variations that are not readily observed in the crystal structures, we used NMR to study WT TTR and three kinetically and/or thermodynamically destabilized pathogenic variants (V30M, L55P, and V122I). Sequence-corrected chemical shifts reveal important structural differences between WT and mutant TTR. The L55P mutation linked to aggressive early onset cardiomyopathy and polyneuropathy induces substantial structural perturbations in bot

SUBMITTER: Leach BI 

PROVIDER: S-EPMC6067956 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature