Structure and activation of the TSH receptor transmembrane domain

Miguel, Ricardo Núñez; Sanders, Jane; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1007/s13317-016-0090-1

Cited by 21 publications

(6 citation statements)

References 92 publications

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“…Thyrotrophic hormone (TSH, thyroid-stimulating hormone) is a heterodimeric glycoprotein with a molecular weight of 28 kDa, composed of two subunits: α (encoded by the gene on chromosome 6) and specific β (encoded by the gene on chromosome 1). TSH receptors (TSHR, thyrotropin-secreting hormone receptors) belong to membrane receptors acting through the class A G protein complex (GPCR, G protein-coupled receptors) [65,66]. It has been found that the cell energy deficit correlates with a decrease in TSH synthesis and secretion [77,78].…”

Section: Thyrotrophic Hormone (Tsh)mentioning

confidence: 99%

The Role of Hormones and Trophic Factors as Components of Preservation Solutions in Protection of Renal Function before Transplantation: A Review of the Literature

Ostróżka-Cieślik

Dolińska

2020

Molecules

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Transplantation is currently a routine method for treating end-stage organ failure. In recent years, there has been some progress in the development of an optimal composition of organ preservation solutions, improving the vital functions of the organ and allowing to extend its storage period until implantation into the recipient. Optimizations are mostly based on commercial solutions, routinely used to store grafts intended for transplantation. The paper reviews hormones with a potential nephroprotective effect, which were used to modify the composition of renal perfusion and preservation solutions. Their effectiveness as ingredients of preservation solutions was analysed based on a literature review. Hormones and trophic factors are innovative preservation solution supplements. They have a pleiotropic effect and affect normal renal function. The expression of receptors for melatonin, prolactin, thyrotropin, corticotropin, prostaglandin E1 and trophic factors was confirmed in the kidneys, which suggests that they are a promising therapeutic target for renal IR (ischemia-reperfusion) injury. They can have anti-inflammatory, antioxidant and anti-apoptotic effects, limiting IR injury.

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Section: Thyrotrophic Hormone (Tsh)mentioning

confidence: 99%

The Role of Hormones and Trophic Factors as Components of Preservation Solutions in Protection of Renal Function before Transplantation: A Review of the Literature

Ostróżka-Cieślik

Dolińska

2020

Molecules

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“…Thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptor (GPHR) subfamily that belongs to the leucine-rich repeat-containing GPCR family (LGR), which includes also follicle-stimulating hormone (FSH), luteinising hormone (LH), and human chorionic gonadotropin (hCG) receptors [19,20]. The TSHR gene is located on chromosome 14q31.1 and spans 190 778 bp, which contains 10 exons [21].…”

Section: Thyroid-stimulating Hormone Receptor (Tshr)mentioning

confidence: 99%

“…Receptor hormonu tyreotropowego jest członkiem podrodziny receptorów hormonów glikoproteinowych (GPHR, glycoprotein hormone receptor), należącej do rodziny receptorów sprzężonych z białkiem G, zawierających powtórzenia bogate w leucynę (LGR). Rodzina ta obejmuje także receptory hormonu folikulotropowego (FSH, follicle-stimulating hormone), luteinizującego (LH, luteinising hormone) i ludzkiej gonadotropiny kosmówkowej (hCG, human chorionic gonadotropin) [19,20]. Gen kodujący TSHR znajdujący się na chromosomie 14q31.1, składa się z 190 778 par zasad i 10 egzonów [21].…”

Section: Receptor Hormonu Tyreotropowego (Tshr)unclassified

Glycosylation of thyroid-stimulating hormone receptor

Korta

Pocheć

2019

Endokrynologia Polska

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Thyroid-stimulating hormone receptor (TSHR) is a typical membrane receptor with 7-transmembrane helix domain (7TMR), coupled to the G protein. The mature receptor, present in the cell membrane, is composed of the A subunit comprising a large extracellular domain, and the B subunit, which consists of a short extracellular fragment anchored in the cell membrane and an intracellular part. The TSH receptor is subject to numerous post-translational modifications that determine its final structure and significantly affect its activity. One of them is glycosylation. TSHR is abundantly N-glycosylated, due to the presence of six N-glycosylation sites in the extracellular domain (Asn77, Asn99, Asn113, Asn177, Asn198, Asn302), mostly evolutionarily conserved. N-glycans constitute 30-40% of the receptor molecular weight. The glycans are necessary for the receptor trafficking to the plasma membrane and binding of TSH to the receptor. Fucosylated and sialylated N-oligosaccharides were found on TSHR molecules. The increased sialylation of TSHR glycans correlates positively with the receptor binding ability and prolongs the time of receptor incorporation into the cell membrane. TSHR is the main autoantigen in Graves' disease (GD), one of the thyroid autoimmune diseases. One hypothesis assumes that the higher N-glycosylation of THSR in human compared to animals influences the breaking of autotolerance and GD development. N-oligosaccharides are the important part of THSR molecule, necessary for the proper functioning of receptors and probably involved in thyroid autoimmunity in GD.

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“…Gly132 is located in the extracellular leucine-rich repeat (LRR) domain of the TSHR. The large concave surface of the TSHR LRR represents the site of interaction between TSHR and TSH, as well as TSHR and its autoantibodies [ 31 ]. Glycine 132 is located on the β strand of the fifth LRR repeat, between residues Phe130 and Phe134, which interact with Lys91 and Tyr88, respectively, in the TSH–TSHR model complex (and with Pro97 in the thyroid-stimulating autoantibody M22–TSHR complex) [ 32 ].…”

Section: Description Of Casesmentioning

confidence: 99%

Structural Biology Helps Interpret Variants of Uncertain Significance in Genes Causing Endocrine and Metabolic Disorders

Ittisoponpisan

David

2018

Journal of the Endocrine Society

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ContextVariants of uncertain significance (VUSs) lack sufficient evidence, in terms of statistical power or experimental studies, to allow unequivocal determination of their damaging effect. VUSs are a major burden in performing genetic analysis. Although in silico prediction tools are widely used, their specificity is low, thus urgently calling for methods for prioritizing and characterizing variants.ObjectiveTo assess the frequency of VUSs in genes causing endocrine and metabolic disorders, the concordance rate of predictions from different in silico methods, and the added value of three-dimensional protein structure analysis in discerning and prioritizing damaging variants.ResultsA total of 12,266 missense variants reported in 641 genes causing endocrine and metabolic disorders were analyzed. Among these, 4123 (33.7%) were VUSs, of which 2010 (48.8%) were predicted to be damaging and 1452 (35.2%) were predicted to be tolerated according to in silico tools. A total of 5383 (87.7%) of 6133 disease-causing variants and 823 (55.8%) of 1474 benign variants were correctly predicted. In silico predictions were noninformative in 5.7%, 14.4%, and 16% of damaging, benign, and VUSs, respectively. A damaging effect on 3D protein structure was present in 240 (30.9%) of predicted damaging and 40 (9.7%) of predicted tolerated VUSs (P < 0.001). An in-depth analysis of nine VUSs occurring in TSHR, LDLR, CASR, and APOE showed that they greatly affect protein stability and are therefore strong candidates for disease.ConclusionsIn our dataset, we confirmed the high sensitivity but low specificity of in silico predictions tools. 3D protein structural analysis is a compelling tool for characterizing and prioritizing VUSs and should be a part of genetic variant analysis.

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Structure and activation of the TSH receptor transmembrane domain

Cited by 21 publications

References 92 publications

The Role of Hormones and Trophic Factors as Components of Preservation Solutions in Protection of Renal Function before Transplantation: A Review of the Literature

The Role of Hormones and Trophic Factors as Components of Preservation Solutions in Protection of Renal Function before Transplantation: A Review of the Literature

Glycosylation of thyroid-stimulating hormone receptor

Structural Biology Helps Interpret Variants of Uncertain Significance in Genes Causing Endocrine and Metabolic Disorders

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