PDBsum entry 3djs

Transport protein

PDB id: 3djs

Contents

Protein chain

116 a.a. *

Waters ×184

* Residue conservation analysis

PDB id:

3djs

Name:

Transport protein

Title:

Crystal structure of transthyretin variant l58h at acidic ph

Structure:

Transthyretin. Chain: a, b. Synonym: prealbumin, tbpa, ttr, attr. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.205 R-free: 0.217

Authors:

L.Cendron,G.Zanotti,C.Folli,R.Berni

Key ref:

L.Cendron et al. (2009). Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses. J Biol Chem, 284, 25832-25841. PubMed id: 19602727

Date:

24-Jun-08 Release date: 14-Jul-09

Protein chains

P02766  (TTHY_HUMAN) -  Transthyretin from Homo sapiens

Seq: 147 a.a.

Struc: 116 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

J Biol Chem 284:25832-25841 (2009)

PubMed id: 19602727

Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses.

L.Cendron, A.Trovato, F.Seno, C.Folli, B.Alfieri, G.Zanotti, R.Berni.

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.