The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution

J. A. Hamilton, L. K. Steinrauf, B. C. Braden, J. Liepnieks, M. D. Benson, G. Holmgren, O. Sandgren, L. Steen

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Abstract

The x-ray crystal structures of normal human transthyretin (prealbumin) and the amyloidogenic Val-30-Met variant have been refined at 1.7-Å resolution to R-values of 0.168 and 0.179, respectively, for 19,882 and 20,362 reflections (Fobs > 2.0σ). Standard deviations for stereochemical parameters are 0.018 and 0.022 Å for bond distances, 0.030 and 0.038 Å for angle distances, and 0.035 and 0.070 Å for planar 1-4 distances. The newly refined normal structure shows improvement over the original structure of Blake and Swan (Blake, C. C. F., and Swan I. D. A. (1971) J. Mol. Biol. 61, 217-224) in stereochemistry and in the conformation of the loop regions. Residues Arg-103, Thr-123, Asn-124, and Pro-125 have now been resolved, and residues 1-9 and 126-127 have been modeled with the aid of simulated annealing refinement. The functional form of transthyretin is a tetramer, having a cylindrical cavity which will bind thyroxine and an exterior binding site for the complex of retinol with retinol-bindingprotein. The monomer is a β barrel flattened to become more like a sandwich with residue 30 in the interior. The methionyl for valyl substitution forces the β sheets of the monomer as much as 1 Å apart, resulting in a distortion of the thyroxine-binding cavity, in agreement with the independent observations that the Met-30 variant has low affinity for thyroxine.

Original languageEnglish (US)
Pages (from-to)2416-2424
Number of pages9
JournalJournal of Biological Chemistry
Volume268
Issue number4
StatePublished - Jan 1 1993

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hamilton, J. A., Steinrauf, L. K., Braden, B. C., Liepnieks, J., Benson, M. D., Holmgren, G., Sandgren, O., & Steen, L. (1993). The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30 → Met variant to 1.7-Å resolution. Journal of Biological Chemistry, 268(4), 2416-2424.