Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

Lábadi, Árpád; Grassi, Elisa; Gellén, Balázs; Kleinau, Gunnar; Biebermann, Heike; Ruzsa, Beata; Gelmini, Giulia; Rideg, Orsolya; Miseta, Attila; Kovaćs, Gábor L.; Patócs, Attila; Felszeghy, Enikő; Nagy, Endre; Mezősi, Emese; Persani, Luca

doi:10.1210/jc.2014-4511

Cited by 19 publications

(17 citation statements)

References 19 publications

(28 reference statements)

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“…These residues are highly conserved across hTAS2Rs (92 and 96% respectively, see Supplementary Table 3 ). Moreover, we notice here that these two positions are also conserved in human class A GPCRs (98 and 87%) and have been shown to play a role for activation across class A hGPCRs, based on mutagenesis data (see references Fenalti et al, 2014 ; Labadi et al, 2015 and Supplementary Table 4 ) and structural analyses (Venkatakrishnan et al, 2013 ; Tehan et al, 2014 ). Therefore, this may further support the claimed role of positions 1.50 and 2.50 for hTAS2Rs activation.…”

Section: Resultsmentioning

confidence: 64%

Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

Fierro

Suku

Alfonso‐Prieto

et al. 2017

Front. Mol. Biosci.

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Human G-protein coupled receptors (hGPCRs) constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.

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Section: Resultsmentioning

confidence: 64%

Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

Fierro

Suku

Alfonso‐Prieto

et al. 2017

Front. Mol. Biosci.

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“…Western Blot experiments were performed as previously reported [ 59 ]. For detection of Phospho-proteins cells were lysed with SDS sample buffer (62.5 mM Tris-HCl pH 6.8, 2% SDS) supplemented with protease and phosphatase inhibitors, immediately heated for 3 min at 95°C and sonicated.…”

Section: Methodsmentioning

confidence: 99%

SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways

et al. 2015

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Thyroid cancer is the most common endocrine malignancy with increasing incidence worldwide.The majority of thyroid cancer cases are well differentiated with favorable outcome. However, undifferentiated thyroid cancers are one of the most lethal human malignancies because of their invasiveness, metastatization and refractoriness even to the most recently developed therapies.In this study we show for the first time a significant hyperactivation of ROCK/HDAC6 pathway in thyroid cancer tissues, and its negative correlation with p53 DNA binding ability.We demonstrate that a small compound, SP600125 (SP), is able to induce cell death selectively in undifferentiated thyroid cancer cell lines by specifically acting on the pathogenic pathways of cancer development. In detail, SP acts on the ROCK/HDAC6 pathway involved in dedifferentiation and invasiveness of undifferentiated human cancers, by restoring its physiological activity level. As main consequence, cancer cell migration is inhibited and, at the same time, cell death is induced through the mitotic catastrophe. Moreover, SP exerts a preferential action on the mutant p53 by increasing its DNA binding ability. In TP53-mutant cells that survive mitotic catastrophe this process results in p21 induction and eventually lead to premature senescence. In conclusion, SP has been proved to be able to simultaneously block cell replication and migration, the two main processes involved in cancer development and dissemination, making it an ideal candidate for developing new drugs against anaplastic thyroid cancer.

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“…(45, 90, 104–107)]. These models were helpful for elucidating mechanisms of pathogenic mutations (26, 108, 109), allosteric small-molecule binding (45, 48, 49, 110), or G-protein and arrestin coupling (111) and guided more rational experimental approaches by suggesting potential interactions or mechanisms, in advance of already available knowledge. These experiments, in turn, were useful for refining or proving model-based predictions.…”

Section: Available Structural Informationmentioning

confidence: 99%

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

et al. 2017

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The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.

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Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

Abstract: TSHR mutations are common among Hungarian patients with CH. The novel genetic alterations revealed an important structural role of the N432(1.50) and the P449(2.39) residues in receptor expression and signaling, respectively.

Cited by 19 publications

References 19 publications

Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

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