The beta-slip: a novel concept in transthyretin amyloidosis.
Transthyretin is a tetrameric plasma protein associated with two forms of amyloid disease. The structure of the highly amyloidogenic transthyretin triple mutant TTRG53S/E54D/L55S determined at 2.3 A resolution reveals a novel conformation: the beta-slip. A three-residue shift in beta strand D places Leu-58 at the position normally occupied by Leu-55 now mutated to serine. The beta-slip is best defined in two of the four monomers, where it makes new protein-protein interactions to an area normally involved in complex formation with retinol-binding protein. This interaction creates unique packing arrangements, where two protein helices combine to form a double helix in agreement with fiber diffraction and electron microscopy data. Based on these findings, a novel model for transthyretin amyloid formation is presented.
Eneqvist
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Umea Center for Molecular Pathogenesis Umea University S-901 87, Umea, Sweden.
Andersson
K
K
Olofsson
A
A
Lundgren
E
E
Sauer-Eriksson
A E
AE
D019943:Amino Acid Substitution / Q000235:genetics; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008854:Microscopy, Electron; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D025941:Protein Interaction Mapping; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
D000939:Epitopes; D011228:Prealbumin