The crystal structure of amyloidogenic Leu55 → Pro transthyretin variant reveals a possible pathway for transthyretin polymerization into amyloid fibrils

Abstract

The x-ray crystal structure of the amyloidogenic Leu55 → Pro transthyretin (TTR) variant, implicated as the causative agent in early- onset familial amyloidotic polyneuropathy (Jacobson, D. R., McFarlin, D. E., Kane I., and Buxbaum, J.N. (1992) Hum. Genet. 89, 353-356), has been solved by molecular replacement, refined at 2.7 Å to a R(cryst) value of 0.190 (F(obs) > 2.0σ), and compared with wild-type transthyretin to understand the molecular mechanism(s) involved in amyloidogenesis. Leu55 → Pro TTR crystallizes in space group C2, with eight monomers in the asymmetric unit, and the observed packing contacts are considerably different from those described for the wild-type protein. Refinement of the crystal structure shows that the proline for leucine substitution disrupts the hydrogen bonds between strands D and A, resulting in different interface contacts. Based on the assumption that the observed packing contacts may be significant for amyloidogenesis, a model for the TTR amyloid is proposed. It consists of a tubular structure with inner and outer diameters approximately of 30 and 100 Å and four monomers per cross-section.