Thyroxine interactions with transthyretin: a comparison of 10 different naturally occurring human transthyretin variants.
Transthyretin (TTR) is a tetrameric protein that transports 15-20% of circulating T4. Alterations in TTR structure can manifest clinically as familial amyloidotic polyneuropathy or euthyroid hyperthyroxinemia. We have measured the relative affinity for T4 of several variant TTR molecules in human plasma. We have compared control plasma to plasma from a patient heterozygous for a [Thr109]TTR mutation associated with a 3-fold increased affinity for T4 and to plasma from patients with familial amyloidotic polyneuropathy with different point mutations in TTR. Relative affinity was measured in an assay in which [125I]T4 bound by TTR was isolated by immunoprecipitation with an antibody specific for TTR. [Thr109]TTR displayed the highest affinity for T4, whereas homozygous [Met30]TTR did not bind appreciable amounts of [125I]T4. The rank order of affinity of the various TTR mutations for T4 was: Thr109 heterozygous > wild type = Ala60 heterozygous = Ile122 heterozygous > His58 heterozygous approximately Tyr77 heterozygous approximately Ser84 heterozygous approximately Ile122 homozygous approximately Met30 heterozygous >> Met30 homozygous TTR. Thus, different point mutations in TTR increase, decrease, or do not affect TTR's affinity for T4. The ability of TTR to form amyloid fibrils does not appear to be related to its affinity for T4. Further study is required to define the molecular basis of alterations in T4 binding induced by point mutations located along the TTR tetramer.
Rosen
H N
HN
Diabetes Unit, Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215.
Moses
A C
AC
Murrell
J R
JR
Liepnieks
J J
JJ
Benson
M D
MD
D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D006579:Heterozygote; D006720:Homozygote; D006980:Hyperthyroidism / Q000235:genetics / Q000378:metabolism; D006981:Hyperthyroxinemia / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism*; D013975:Thyroxine-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D011228:Prealbumin; D013975:Thyroxine-Binding Proteins; D013974:Thyroxine