TERTIARY STRUCTURES OF AMYLOIDOGENIC AND NON-AMYLOIDOGENIC TRANSTHYRETIN VARIANTS - NEW MODEL FOR AMYLOID FIBRIL FORMATION

The most common form of hereditary systemic amyloidosis is familial am yloidotic polyneuropathy associated with single amino acid changes in the plasma protein transthyretin. So far, high resolution structures o f only three amyloidogenic variants (Met30, Ser84, Ile122) and one non -amyloidogenic variant (Thr109) have been reported complemented by X-r ay fiber diffraction studies and image reconstruction from electron mi crographs of amyloid fibrils. To investigate the role of structural fa ctors in this disease, we extended our studies to other transthyretin variants. We report crystallization and structural investigations of t hree amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic var iants (Ser6, Met119). The similarity of these structures to normal tra nsthyretin does not give direct clues to the fibril forming process. S ince transthyretin amyloid fibrils contain a major fragment starting a t position 49, besides the intact molecule, we calculated the solvent accessibility of residue 48. Indeed, all amyloidogenic variants show a n increased main chain solvent exposure when compared to normal transt hyretin and non-amyloidogenic variants, which can be postulated to res ult in increased susceptibility to proteolysis. After limited proteoly sis, dimers are incapable of reassociation to native tetramers. We pre sent a model for amyloid fibril formation based on formation of fibril s from N-terminal truncated dimers as building blocks.