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.

Keyword

Amino Acid Substitution/genetics

Amyloidosis/genetics/*metabolism

Binding Sites

Crystallography; X-Ray

Epitopes/chemistry/metabolism

Humans

Hydrogen Bonding

Microscopy; Electron

Models; Biological

Models; Molecular

Mutation/genetics

Prealbumin/*chemistry/genetics/*metabolism

Protein Binding

Protein Folding

Protein Interaction Mapping

Protein Structure; Quaternary

Protein Structure; Secondary

Publication and Content Type

ref (subject category)

art (subject category)