Tertiary structures of amyloidogenic and non-amyloidogenic transthyretin variants: new model for amyloid fibril formation

Abstract

The most common form of hereditary systemic amyloidosis is familial amyloidotic poly neuropathy associated with single amino acid changes in the plasma protein transthyretin.

So far, high resolution structures of only three amyloidogenic variants (Met30, Ser84, tle 122) and one non-amyloidogenic variant (Thr109) have been reported complemented by X-ray fiber diffraction studies and image reconstruction from electron micrographs of amyloid fibrils

To investigate the role of structural factors in this disease, we extended our studies to other transthyretin variants. We report crystallization and structural investigations of three amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic variants (Ser6, Met119). The similarity oj these structures to normal transthyretin does not give direct clues to the fibril forming process. Since transthyretin amyloid fibrils contain a major fragment starting at position 49, besides the intact molecule, we calculated the solvent accessibility of residue 48. Indeed, all amyloidogenic variants show an increased main chain solvent exposure when compared to normal transthyretin and non-amyloidogenic variants, which can be postulated to result in increased susceptibility to proteolysis. Affer limited proteolysis, dimers are incapable ofreassociation to native telramers

We present a model for amyloid fibril formation based on formation of fibrils from N-terminal truncated dimers as building blocks.

Key Words:

• transthyretin
• crystal structures
• hereditary amyloidosis
• fibril model