3DK0: Crystal Structure Of Transthyretin Variant L55p At Acidic Ph

Citation:
Abstract
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 beta-aggregation. We report the results of a computational analysis predicting that wild-type TTR possesses a very high intrinsic beta-aggregation propensity which is on average not enhanced by amyloidogenic mutations. However, when located in beta-strands, most of these mutations are predicted to destabilize the native beta-structure. The analysis also shows that rat and murine TTR have a lower intrinsic beta-aggregation propensity and a similar native beta-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 beta-aggregation propensity.
PDB ID: 3DK0Download
MMDB ID: 75285
PDB Deposition Date: 2008/6/24
Updated in MMDB: 2009/07
Experimental Method:
x-ray diffraction
Resolution: 1.87  Å
Source Organism:
Similar Structures:
Biological Unit for 3DK0: tetrameric; determined by author and by software (PISA)
Molecular Components in 3DK0
Label Count Molecule
Proteins (4 molecules)
4
Transthyretin(Gene symbol: TTR)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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