Thyroxine binding to transthyretin (TTR) variants--two variants (TTR Pro 55 and TTR Met 111) with a particularly low binding affinity.
Thyroxine (T4) binding is a well-characterized function of transthyretin (TTR) and has been used to assess structural alterations of TTR variants. Most TTR variants deposit as amyloid fibrils originating different forms of hereditary amyloidosis. It has been hypothesized that amino acid substitutions in the TTR variants induce structural alterations that may be responsible for the amyloidogenicity of the mutant proteins. To test for structural alterations in TTR, we studied T4 binding to TTR variants both in whole serum and in isolated form obtained from heterozygotic carriers of amyloidogenic and non-amyloidogenic variants and compared the binding with the corresponding homozygotic recombinant variants. The results obtained indicated a normal T4 binding affinity for heterozygotic TTR Ala 49, TTR Leu 68, TTR Ala 71 and TTR Arg 102. Concerning TTR Pro 55 and TTR Met 111, we found a consistent decrease in binding affinity. These results were more pronounced for the equivalent recombinant proteins. Recombinant TTR Pro 55 did not show specific binding to T4 and recombinant TTR Met 111 presented very low binding affinity. Neither TTR Pro 55 nor TTR Met 111 are localized in the T4 binding channel, thus structural alterations induced by these mutations should be transmitted to the binding channel interfering with T4 binding. The results now reported, together with ongoing structural data by X-ray analyses on mutants Pro 55 and Met 111 and future binding studies with other ligands, will contribute to the elucidation of the structure and function of TTR, particularly in thyroid hormone metabolism.
Almeida
M R
MR
Centro de Estudos de Paramiloidose, Hospital de Santo António, Universidade do Porto, Portugal.
Saraiva
M J
MJ
D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins; D011995:Recombination, Genetic; D013974:Thyroxine / Q000097:blood / Q000378:metabolism*
D000682:Amyloid; D011228:Prealbumin; D011994:Recombinant Proteins; D013974:Thyroxine