Specific activation of the thyrotropin receptor by trypsin

Sande, Jacqueline Van; Massart, C.; Costagliola, Sabine; Allgeier, Anouk; Cetani, Filomena; Vassart, Gilbert; Dumont, Jacques Emile

doi:10.1016/0303-7207(96)03804-x

Cited by 73 publications

(54 citation statements)

References 31 publications

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“…These findings indicate that removal of the ECD does not enhance basal LHR activity, and thus, that the ECD in the case of the LHR does not serve as a tethered inverse agonist. These results are in line with previous studies (Sangkuhl et al 2002, Karges et al 2005 and in clear contrast to the model proposed for the TSHR (Zhang et al 1995, Van Sande et al 1996, Gruters et al 1998, Nakabayashi et al 2000, Nishi et al 2002, Vlaeminck-Guillem et al 2002. The absence of the ECD in V2LHR or the partial deletion of the ECD in V2hingeLHR reduced basal receptor activity, suggesting a putative role of the ECD as a positive, but not as a negative regulator of receptor activity.…”

Section: Resultssupporting

confidence: 91%

“…However, both domains cooperate in intramolecular signal transmission. Thus, the concept has been put forward that the ECD of the TSHR acts as an inverse agonist to constrain the TMD in an inactive conformation (Zhang et al 1995, Van Sande et al 1996, Gruters et al 1998, Nakabayashi et al 2000, Nishi et al 2002, Vlaeminck--Guillem et al 2002. To investigate whether this is also the case for the human LHR, a receptor mutant (V2LHR) lacking the complete ECD was examined (Table 1; Sangkuhl et al 2002).…”

Section: Resultsmentioning

confidence: 99%

“…In a second model, particularly proposed for the TSH receptor (TSHR), the ECD serves as an inverse agonist stabilizing the transmembrane helices in an inactive conformation. This model implies that hormone binding and activating mutations disengage the inhibitory ECD-TMD interaction (Zhang et al 1995, Van Sande et al 1996, Gruters et al 1998, Nakabayashi et al 2000, Nishi et al 2002, Vlaeminck-Guillem et al 2002 and is supported by findings that removal of the complete ECD leads to high constitutive receptor activity (Zhang et al 2000). Consistent with this hypothesis, deletion of portions of the ECD (Zhang et al 1995) or activating mutations within the ECD (Gruters et al 1998, Nakabayashi et al 2000 can result in elevated basal activity.…”

Section: Introductionmentioning

confidence: 88%

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A conformational contribution of the luteinizing hormone–receptor ectodomain to receptor activation

Nurwakagari

Breit²,

Heß³

et al. 2007

Journal of Molecular Endocrinology

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Glycoprotein hormone receptors such as the lutropin/chorionic gonadotropin receptor (LHR) are characterized by a large N-terminal ectodomain (ECD), which is responsible for hormone-receptor interactions. For the closely related TSH receptor (TSHR), it has been proposed that the ECD also serves as a tethered inverse agonist. However, the exact role of the LHR-ECD for receptor activation remains elusive. Functional analysis of N-terminally truncated LHR mutants expressed in COS-7 cells revealed that the LHR-ECD does not act as an inverse agonist but facilitates active LHR conformations. This notion is supported by two observations: first, removal of the ECD tended to decrease basal LHR activity and secondly, mutationally induced constitutive receptor activity was diminished for most activating mutations in LHR lacking the ECD. In addition, swapping of the LHR-ECD for the ECD of the closely related TSHR was not sufficient to restore constitutive receptor activity induced by naturally occurring activating heptahelical LHR mutations. Thus, the ECD stabilizes an activation-competent conformation of the heptahelical region. While the full-length LHR fused to the cognate agonist, human chorionic gonadotropin (hCG), showed increased basal activity, fusion proteins between hCG and Nterminally truncated LHR did not yield constitutive receptor activity suggesting an important role of the ECD also for agonist-dependent LHR activity. Our experiments strengthen the concept of a major contribution of the LHR-ECD in the activation mechanism apart from hormone binding and provide evidence for a cooperative model with structural and functional interactions of the ECD and the transmembrane domain.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

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A conformational contribution of the luteinizing hormone–receptor ectodomain to receptor activation

Nurwakagari

Breit²,

Heß³

et al. 2007

Journal of Molecular Endocrinology

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“…Even with the remarkable similarity in the receptor architecture, the mechanistic basis of such differential basal receptor activation has been not well elucidated. Removal of the ECD from TSHR further increased the relatively high basal cAMP production, similar to that reported earlier (48). This increase has been attributed to the tethered inverse agonistic effect of the TSHR ECD where the ECD keeps the TMD in an inactive state (49), and this inverse agonism has been narrowed down to the HinR of TSHR where specific contacts between the residues of HinR and ECLs are primarily responsible for the hinge-TMD constraint (50).…”

Section: Spatial Organization Of the Loops In The Resting And Hormonesupporting

confidence: 79%

The Antibodies against the Computationally Designed Mimic of the Glycoprotein Hormone Receptor Transmembrane Domain Provide Insights into Receptor Activation and Suppress the Constitutively Activated Receptor Mutants

Majumdar

Railkar²,

Dighe

2012

Journal of Biological Chemistry

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Background:The mechanism of glycoprotein hormone receptor activation is not clearly understood. Results: Antibodies against computationally designed TMD mimic bind TSHR/LHR/FSHR and inhibit hormone-independent and -dependent receptor activation without affecting respective hormone binding. Conclusion: Conformational alterations in transmembrane helices leading to receptor activation are dependent on changes in hinge-exoloop engagements. Significance: Antibodies against novel TMD mimic have therapeutic potential against gain-of-function diseases and provide insights into receptor activation.

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“…Proteolytic degradation (19), deletions in the ectodomain region 339 -367 (20) or the deletion of the entire extracellular domain (ECD) (17) also lead to constitutive TSHR activation. Zhang et al (17) postulated that the functionally intact ectodomain plays a key role in stabilizing the inactive conformation of the TSHR as an internal antagonist.…”

Section: Introductionmentioning

confidence: 99%

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation

Neumann

Claus²,

Paschke

2005

eur j endocrinol

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Objective: The molecular mechanisms of TSH receptor (TSHR) activation and intramolecular signal transduction are largely unknown. Deletion of the extracellular domain (ECD) of the TSHR results in increased constitutive activity, which suggests a self-inhibitory interaction between the ECD and the extracellular loops (ECLs) or the transmembrane domains (TMDs). To investigate these potential interactions and to pursue the idea that mutations in the ECD affect the constitutive activity of mutants in the ECLs or TMDs we generated double mutants between position 281 in the ECD and mutants in all three ECLs as well as the 6th TMD. Design: We combined mutation S281D, characterized by an impaired TSH-stimulated cAMP response, with the constitutively activating in vivo mutations I486F (1st ECL), I568T (2nd ECL), V656F (3rd ECL) and D633F (6th TMD). Further, we constructed double mutants containing the constitutively activating mutation S281N and one of the inactivating mutations D474E, T477I (1st ECL) and D633K (6th TMD). Results: The cAMP level of the double mutants with S281N and the inactive mutants in the 1st ECL was decreased below the level of the inactive single mutants, demonstrating that a constitutively activating mutation in the ECD cannot bypass disruption of signal transduction in the serpentine domain. In double mutants with S281D, basal and TSH-induced cAMP and inositol phosphate production of constitutively active mutants was reduced to the level of S281D. Conclusion: The dominance of S281D and the dependence of constitutively activating mutations in the ECLs on the functionally intact ECD strongly suggest that interactions between these receptor domains are required for TSHR activation and intramolecular signal transduction.European Journal of Endocrinology 152 625-634

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Specific activation of the thyrotropin receptor by trypsin

Cited by 73 publications

References 31 publications

A conformational contribution of the luteinizing hormone–receptor ectodomain to receptor activation

A conformational contribution of the luteinizing hormone–receptor ectodomain to receptor activation

The Antibodies against the Computationally Designed Mimic of the Glycoprotein Hormone Receptor Transmembrane Domain Provide Insights into Receptor Activation and Suppress the Constitutively Activated Receptor Mutants

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation

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