3D-STRUCTURE OF HUMAN TRANSTHYRETIN LEU-55-PRO MUTANT. Paula Sebastiao¹, Zbigniew Dauter², Maria Joao Saraiva² and Ana Margarida Damas², Embl, c/o Desy, Notkestrasse 85, 22607 Hamburg, Germany¹, Instituto de Ciencias Biomedicas de Abel Salazar, Largo Prof. Abel Salazar, 4000 Porto, Portugal²

The aim of the present study is the elucidation of the molecular mechanism(s) involved in amyloidogenesis by the structural characterization of transthyretin (TTR) variants.

The 3D-structure of variant human transthyretin Leu-55-Pro implicated as the causative agent in early-onset Familial Amyloid Polyneuropathy (FAP) is presented and the molecular mechanism involved in its extreme pathogenecity is suggested. FAP is an autosomal dominant disease characterised by the systemic deposition of amyloid with a particular involvement of the peripheral nerves. Amyloid FAP fibril formation is due to TTR aggregation in an insoluble protease resistant fibril with an antiparallel ß-pleated sheet structure which leads to neurotoxicity and organ dysfunction.

Transthyretin (TTR) also known as thyroxine-binding prealbumin is a tetrameric human plasma protein (MW 54980) composed of identical 127 residue subunits, each having a ß-sheet structure. Each monomer subunit presents two four-stranded ß-sheets Dagh (inner-sheet) and Cbef (outersheet).

The molecular characterization of this amyloidogenic TTR variant showed that the Leu-55-Pro mutation disrupts ß-strand D involved in the inner ß-sheet Dagh. The electrostatic surface potential in this TTR variant differs from that in the wild-type protein. Pathological effects may arise as this enhances the oligomerization of the protein and/or interaction of transthyretin with other amyloid components namely glycosaminoglycans.