Resistance to thyroid hormone (RTH) syndrome reveals novel determinants regulating interaction of T3 receptor with corepressor.
Thyroid hormone receptors (T3Rs) both repress and activate gene transcription by interacting with auxiliary factors denoted corepressors and coactivators. Resistance to thyroid hormone (RTH) syndrome in humans is manifested as a failure to respond properly to elevated circulating thyroid hormone. RTH syndrome has been mapped to T3Rbeta mutations that alter the transcriptional properties of the receptor, resulting in a dominant negative phenotype. We report here a characterization of a series of RTH mutant T3Rs that exhibit unusual interactions with corepressor. Two mutations in receptor helix 11 (delta430, delta432) greatly enhance the ability of the mutant receptors to bind to corepressor. A distinct mutation, V264D, in an 'omega loop' region of the receptor, impairs corepressor release but does not fully eliminate the ability to recruit coactivator. These mutations reveal novel determinants that regulate the interaction of the T3R with important ancillary cofactors, and that are disrupted in a human endocrine disease.
Yoh
S M
SM
Division of Biological Sciences, University of California at Davis, 95616, USA. mlprivalsky@ucdavis.edu
Privalsky
M L
ML
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056985:Nuclear Receptor Co-Repressor 2; D010641:Phenotype; D017354:Point Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins