Amyloidogenic Potential of Transthyretin Variants: INSIGHTS FROM STRUCTURAL AND COMPUTATIONAL ANALYSES*
AUTOR(ES)
Cendron, Laura
FONTE
American Society for Biochemistry and Molecular Biology
RESUMO
Human transthyretin (TTR) is an amyloidogenic protein whose mild amyloidogenicity is enhanced by many point mutations affecting considerably the amyloid disease phenotype. To ascertain whether the high amyloidogenic potential of TTR variants may be explained on the basis of the conformational change hypothesis, an aim of this work was to determine structural alterations for five amyloidogenic TTR variants crystallized under native and/or destabilizing (moderately acidic pH) conditions. While at acidic pH structural changes may be more significant because of a higher local protein flexibility, only limited alterations, possibly representing early events associated with protein destabilization, are generally induced by mutations. This study was also aimed at establishing to what extent wild-type TTR and its amyloidogenic variants are intrinsically prone to β-aggregation. We report the results of a computational analysis predicting that wild-type TTR possesses a very high intrinsic β-aggregation propensity which is on average not enhanced by amyloidogenic mutations. However, when located in β-strands, most of these mutations are predicted to destabilize the native β-structure. The analysis also shows that rat and murine TTR have a lower intrinsic β-aggregation propensity and a similar native β-structure stability compared with human TTR. This result is consistent with the lack of in vitro amyloidogenicity found for both murine and rat TTR. Collectively, the results of this study support the notion that the high amyloidogenic potential of human pathogenic TTR variants is determined by the destabilization of their native structures, rather than by a higher intrinsic β-aggregation propensity.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2757985Documentos Relacionados
- Structural flexibility of isozyme variants: genetic variants in Drosophila disguised by cofactor and subunit binding.
- Structure of Met30 variant of transthyretin and its amyloidogenic implications.
- The preaggregated state of an amyloidogenic protein: Hydrostatic pressure converts native transthyretin into the amyloidogenic state
- Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals
- Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants