title: 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 A to a Rcryst value of 0.190 (Fobs > 2.0sigma), 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 A and four monomers per cross-section.
authors.affiliation: Instituto de Biologia Molecular e Celular, Rua do Campo Alegre, no. 823, 4150 Porto, Portugal.
authors.forename: M P
authors.initials: MP
authors.lastname: Sebastião
authors.forename: M J
authors.initials: MJ
authors.lastname: Saraiva
authors.forename: A M
authors.initials: AM
authors.lastname: Damas
mesh_terms: D000595:Amino Acid Sequence; D017772:Amyloid Neuropathies / Q000235:genetics; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods; D014644:Genetic Variation; D006801:Humans; D007930:Leucine; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011392:Proline; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D046911:Macromolecular Substances; D011228:Prealbumin; D011994:Recombinant Proteins; D011392:Proline; D007930:Leucine