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Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain.

Huber BR, Desclozeaux M, West BL, Cunha-Lima ST, Nguyen HT, Baxter JD, Ingraham HA, Fletterick RJ
Mol Endocrinol 17 107-16 (2003)
Cited: 18 times
EuropePMC logo PMID: 12511610

Abstract

Resistance to thyroid hormone (RTH) syndrome is associated with mutations in the human thyroid hormone receptor-beta (hTRbeta), many of which show marked reduction in hormone binding. Here, we investigated the structural consequences of two RTH mutants (A234T and R243Q), residing in the flexible N-terminal portion of the ligand binding domain (LBD), which exhibit modestly reduced hormone binding with impaired release of corepressor. X-ray crystallography analyses revealed that these two RTH mutants modulate the position of this flexible region by either altering the movement of helix 1 (A234T) or disrupting a salt bridge (R243Q). The subsequent increased flexibility and mobility in regions after the two sites of mutation coincided with a disorganized LBD. Consistent with this finding, the ability of these mutant N-terminal regions (234-260) to recruit the remaining LBD was decreased in a ligand-dependent helix assembly assay. Collectively, these data suggest that structural information imparted by the flexible segment in the N-terminal LBD is critical for overall stability of the LBD. Thus, these structural analyses provide mechanistic insight into the etiology of RTH disease in human TRbeta mutants that exhibit hormone binding with decreased ligand-dependent corepressor release.

Articles - 1nq0 mentioned but not cited (3)

  1. Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. Mysinger MM, Carchia M, Irwin JJ, Shoichet BK. J Med Chem 55 6582-6594 (2012)
  2. Halogen bonds in biological molecules. Auffinger P, Hays FA, Westhof E, Ho PS. Proc Natl Acad Sci U S A 101 16789-16794 (2004)
  3. Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors. Martínez L, Sonoda MT, Webb P, Baxter JD, Skaf MS, Polikarpov I. Biophys J 89 2011-2023 (2005)


Reviews citing this publication (3)

  1. Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Cheng SY. Trends Endocrinol Metab 16 176-182 (2005)
  2. Conformational adaptation of nuclear receptor ligand binding domains to agonists: potential for novel approaches to ligand design. Togashi M, Borngraeber S, Sandler B, Fletterick RJ, Webb P, Baxter JD. J Steroid Biochem Mol Biol 93 127-137 (2005)
  3. Genetic features of thyroid hormone receptors. Rebaï M, Kallel I, Rebaï A. J Genet 91 367-374 (2012)

Articles citing this publication (12)

  1. Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Sablin EP, Krylova IN, Fletterick RJ, Ingraham HA. Mol Cell 11 1575-1585 (2003)
  2. A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. Liu YY, Schultz JJ, Brent GA. J Biol Chem 278 38913-38920 (2003)
  3. Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, Baxter JD, Scanlan TS, Fletterick RJ. Proc Natl Acad Sci U S A 100 15358-15363 (2003)
  4. Alternative mRNA splicing of SMRT creates functional diversity by generating corepressor isoforms with different affinities for different nuclear receptors. Goodson ML, Jonas BA, Privalsky ML. J Biol Chem 280 7493-7503 (2005)
  5. Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations. Peräkylä M. Eur Biophys J 38 185-198 (2009)
  6. The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions. Harvey CB, Bassett JH, Maruvada P, Yen PM, Williams GR. Endocrinology 148 1764-1773 (2007)
  7. A natural polymorphism in peroxisome proliferator-activated receptor-alpha hinge region attenuates transcription due to defective release of nuclear receptor corepressor from chromatin. Liu MH, Li J, Shen P, Husna B, Tai ES, Yong EL. Mol Endocrinol 22 1078-1092 (2008)
  8. Revealing a Mutant-Induced Receptor Allosteric Mechanism for the Thyroid Hormone Resistance. Yao B, Wei Y, Zhang S, Tian S, Xu S, Wang R, Zheng W, Li Y. iScience 20 489-496 (2019)
  9. Unique functional properties of a member of the Fushi Tarazu-Factor 1 family from Schistosoma mansoni. Bertin B, Sasorith S, Caby S, Oger F, Cornette J, Wurtz JM, Pierce RJ. Biochem J 382 337-351 (2004)
  10. DNA-based diagnosis of thyroid hormone resistance syndrome: a novel THRB mutation associated with mild resistance to thyroid hormone. Lam CW, On-Kei Chan A, Tong SF, Shek CC, Cheung Tiu S. Clin Chim Acta 358 55-59 (2005)
  11. Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways. Cunha Lima ST, Nguyen NH, Togashi M, Apriletti JW, Nguyen P, Polikarpov I, Scanlan TS, Baxter JD, Webb P. J Steroid Biochem Mol Biol 117 125-131 (2009)
  12. Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family. Verma S, Chakraborti S, Singh OP, Pande V, Dixit R, Pandey AV, Pandey KC. Front Endocrinol (Lausanne) 13 981090 (2022)


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