ArticleThe Journal of biological chemistry2009
The superagonistic activity of bovine thyroid-stimulating hormone (TSH) and the human TR1401 TSH analog is determined by specific amino acids in the hinge region of the human TSH receptor.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- TSHR in thyroid cancer: bridging biological insights to targeted strategies.European thyroid journal · 2025Review
- Characterization of a human thyroid microtissue model for testing thyroid disrupting chemicals.Frontiers in toxicology · 2024Article
- Obesity and Thyroid Axis.International journal of environmental research and public health · 2021Review
- Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by GMolecular pharmacology · 2020Article
- TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts.Investigative ophthalmology & visual science · 2019Article
- Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.Frontiers in endocrinology · 2017Review
- Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation.The Journal of biological chemistry · 2016Article
- Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves' disease.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies.Expert opinion on therapeutic targets · 2015Review
- Differences in Signal Activation by LH and hCG are Mediated by the LH/CG Receptor's Extracellular Hinge Region.Frontiers in endocrinology · 2015Article
- New Frontier in Glycoprotein Hormones and Their Receptors Structure-Function.Frontiers in endocrinology · 2015Review
- (99m)Tc-labeled-rhTSH analogue (TR1401) for imaging poorly differentiated metastatic thyroid cancer.Thyroid : official journal of the American Thyroid Association · 2014Article
- Influence of the hinge region and its adjacent domains on binding and signaling patterns of the thyrotropin and follitropin receptor.PloS one · 2014Article
- Allosteric modulators hit the TSH receptor.Endocrinology · 2014Article
- Novel insights on thyroid-stimulating hormone receptor signal transduction.Endocrine reviews · 2013Review
- Research resource: novel structural insights bridge gaps in glycoprotein hormone receptor analyses.Molecular endocrinology (Baltimore, Md.) · 2013Article
- Blocking type TSH receptor antibodies.Auto- immunity highlights · 2013Review
- The thyrotropin receptor hinge region as a surrogate ligand: identification of loci contributing to the coupling of thyrotropin binding and receptor activation.Endocrinology · 2012Article
- Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor.Best practice & research. Clinical endocrinology & metabolism · 2012Review
- A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in graves' orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody.The Journal of clinical endocrinology and metabolism · 2012Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bovine TSH (bTSH) has a higher affinity to the human TSHR (hTSHR) and a higher signaling activity than human TSH (hTSH). The molecular reasons for these phenomena are unknown. Distinct negatively charged residues (Glu297, Glu303, and Asp382) in the hinge region of the hTSHR are known to be important for bTSH binding and signaling. To investigate the potential relevance of these positions for differences between bTSH and hTSH in the interaction to the hTSHR, we determined bTSH- and hTSH-mediated cAMP production of several substitutions at these three hinge residues. To examine specific variations of hTSH, we also investigated the superagonistic hTSH analog TR1401 (TR1401), whose sequence differs from hTSH by four additional positively charged amino acids that are also present in bTSH. To characterize possible interactions between the acidic hTSHR positions Glu297, Glu303, or Asp382 and the additional basic residues of TR1401, we investigated TR1401 binding and signaling properties. Our data reveal increased cAMP signaling of the hTSHR using TR1401 and bTSH compared with hTSH. Whereas Asp382 seems to be important for bTSH- and TR1401-mediated but not for hTSH-mediated signaling, the substitution E297K exhibits a decreased signaling for all three TSH variants. Interestingly, bTSH and TR1401 showed only a slightly different binding pattern. These observations imply that specific residues of the hinge region are mediators of the superagonistic activity of bTSH and TR1401 in contrast to hTSH. Moreover, the simultaneous localization of binding components in the glycoprotein hormone molecule and the receptor hinge region permits important reevaluation of interacting hormone receptor domains.
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