A comparative analysis of 23 structures of the amyloidogenic protein transthyretin

Self-assembly of the human plasma protein transthyretin (TTR) into unbranched insoluble amyloid fibrils occurs as a result of point mutations that destabilize the molecule, leading to conformational changes. The tertiary structure of native soluble TTR and many of its disease-causing mutants have be...

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Bibliographic Details
Published in:Journal of molecular biology 2000-09, Vol.302 (3), p.649-669
Main Authors: Hörnberg, Andreas, Eneqvist, Therese, Olofsson, Anders, Lundgren, Erik, Sauer-Eriksson, A.Elisabeth
Format: Article
Language:English
Subjects:
amyloidosis
Crystallography, X-Ray
Dimerization
Electrostatics
familial amyloidotic polyneuropathy
Genetic Variation
Humans
Hydrogen Bonding
Hydrogen-Ion Concentration
Models, Molecular
Molecular Sequence Data
Mutation
Plaque, Amyloid - chemistry
Plaque, Amyloid - genetics
Prealbumin - chemistry
Prealbumin - genetics
Prealbumin - metabolism
Prealbumin/chemistry/genetics/metabolism
Protein Structure, Secondary
Protein Structure, Tertiary
Senile Plaques/chemistry/genetics
Solubility
Solvents
Static Electricity
structural comparison
transthyretin
Variation (Genetics)
Water - metabolism
X-ray structure
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Summary:Self-assembly of the human plasma protein transthyretin (TTR) into unbranched insoluble amyloid fibrils occurs as a result of point mutations that destabilize the molecule, leading to conformational changes. The tertiary structure of native soluble TTR and many of its disease-causing mutants have been determined. Several independent studies by X-ray crystallography have suggested structural differences between TTR variants which are claimed to be of significance for amyloid formation. As these changes are minor and not consistent between the studies, we have compared all TTR structures available at the protein data bank including three wild-types, three non-amyloidogenic mutants, seven amyloidogenic mutants and nine complexes. The reference for this study is a new 1.5 Å resolution structure of human wild-type TTR refined to an R-factor/ R-free of 18.6 %/21.6 %. The present findings are discussed in the light of the previous structural studies of TTR variants, and show the reported structural differences to be non-significant.
ISSN:0022-2836
1089-8638
DOI:10.1006/jmbi.2000.4078