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 Å resolution reveals a novel conformation: the β-slip. A three-residue shift in β strand D places Leu-58 at the position normally occupied by Leu-55 now mutated to serine. The β-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.
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