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

J Biol Chem. 1998 Sep 18;273(38):24715-22. doi: 10.1074/jbc.273.38.24715.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid Neuropathies / genetics
  • Computer Simulation
  • Crystallography, X-Ray / methods
  • Genetic Variation*
  • Humans
  • Leucine*
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • Point Mutation
  • Prealbumin / chemistry*
  • Prealbumin / genetics
  • Prealbumin / metabolism
  • Proline*
  • Protein Conformation*
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry

Substances

  • Macromolecular Substances
  • Prealbumin
  • Recombinant Proteins
  • Proline
  • Leucine

Associated data

  • PDB/5TTR