The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution.
The x-ray crystal structures of normal human transthyretin (prealbumin) and the amyloidogenic Val-30-Met variant have been refined at 1.7-A resolution to R-values of 0.168 and 0.179, respectively, for 19,882 and 20,362 reflections (Fobs > 2.0 sigma). Standard deviations for stereochemical parameters are 0.018 and 0.022 A for bond distances, 0.030 and 0.038 A for angle distances, and 0.035 and 0.070 A 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-binding protein. The monomer is a beta barrel flattened to become more like a sandwich with residue 30 in the interior. The methionyl for valyl substitution forces the beta sheets of the monomer as much as 1 A 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.
Hamilton
J A
JA
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis 46202-5122.
Steinrauf
L K
LK
Braden
B C
BC
Liepnieks
J
J
Benson
M D
MD
Holmgren
G
G
Sandgren
O
O
Steen
L
L
D000595:Amino Acid Sequence; D000682:Amyloid; D003461:Crystallography; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011228:Prealbumin / Q000737:chemistry / Q000648:ultrastructure*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000682:Amyloid; D011228:Prealbumin