3DJR

CRYSTAL STRUCTURE OF TRANSTHYRETIN VARIANT L58H at neutral pH

Summary for 3DJR

• Entry DOI: 10.2210/pdb3djr/pdb
• Related: 1F41 2G4E 2NOY 3DJS 3DJT 3DJZ 3DK0 3DK2
• Descriptor: Transthyretin (2 entities in total)
• Functional Keywords: ttr, amyloid fibrils, point mutation, transport protein, amyloid, disease mutation, gamma-carboxyglutamic acid, glycoprotein, hormone, polyneuropathy, retinol-binding, secreted, thyroid hormone, transport, vitamin a
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 27604.70

Authors

Cendron, L.,Zanotti, G.,Folli, C.,Berni, R. (deposition date: 2008-06-24, release date: 2009-07-14, Last modification date: 2023-11-01)

Primary citation

Cendron, L.,Trovato, A.,Seno, F.,Folli, C.,Alfieri, B.,Zanotti, G.,Berni, R.
Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses.
J.Biol.Chem., 284:25832-25841, 2009

PubMed 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.

PubMed: 19602727
DOI: 10.1074/jbc.M109.017657

Experimental method

X-RAY DIFFRACTION (2.02 Å)