The beta-slip: A novel concept in transthyretin amyloidosis

Transthyretin is a tetrameric plasma protein associated with two forms of a myloid disease. The structure of the highly amyloidogenic transthyretin tri ple mutant TTRG53S/E54D/L55S determined at 2.3 Angstrom 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 i t makes new protein-protein interactions to an area normally involved in co mplex formation with retinol-binding protein. This interaction creates uniq ue packing arrangements, where two protein helices combine to form a double helix in agreement with fiber diffraction and electron microscopy data. Ba sed on these findings, a novel model for transthyretin amyloid formation is presented.