scholarly journals Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation

2016 ◽  
Vol 291 (27) ◽  
pp. 14095-14108 ◽  
Author(s):  
Joerg Schaarschmidt ◽  
Marcus B. M. Nagel ◽  
Sandra Huth ◽  
Holger Jaeschke ◽  
Rocco Moretti ◽  
...  
Keyword(s):  
Extracellular Domain ◽  
Receptor Activation ◽  
Thyrotropin Receptor ◽  
Extracellular Loop

scholarly journals An Inactivating Mutation within the First Extracellular Loop of the Thyrotropin Receptor Impedes Normal Posttranslational Maturation of the Extracellular Domain

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 1043-1050 ◽  
Author(s):  
Sylvia Sura-Trueba ◽  
Chantal Aumas ◽  
Aurore Carre ◽  
Sylvie Durif ◽  
Juliane Leger ◽  
...  
Keyword(s):  
Extracellular Domain ◽  
Thyrotropin Receptor ◽  
Extracellular Loop ◽  
Inactivating Mutation

scholarly journals Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Has a Critical Role in GLP-1 Peptide Binding and Receptor Activation

2011 ◽  
Vol 287 (6) ◽  
pp. 3642-3658 ◽  
Author(s):  
Cassandra Koole ◽  
Denise Wootten ◽  
John Simms ◽  
Laurence J. Miller ◽  
Arthur Christopoulos ◽  
...  
Keyword(s):  
Critical Role ◽  
Peptide Binding ◽  
Receptor Activation ◽  
Extracellular Loop ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Purification and Characterization of a Soluble Bioactive Amino-Terminal Extracellular Domain of the Human Thyrotropin Receptor†

Biochemistry ◽  
2001 ◽  
Vol 40 (33) ◽  
pp. 9860-9869 ◽  
Author(s):  
Sabine Cornelis ◽  
Sandrine Uttenweiler-Joseph ◽  
Valérie Panneels ◽  
Gilbert Vassart ◽  
Sabine Costagliola
Keyword(s):  
Extracellular Domain ◽  
Thyrotropin Receptor ◽  
Purification And Characterization ◽  
Amino Terminal

Disruption of the first extracellular loop of thyrotropin receptor prevents ligand binding

Life Sciences ◽  
1994 ◽  
Vol 55 (12) ◽  
pp. 961-968 ◽  
Author(s):  
K. Haraguchi ◽  
T. Saito ◽  
T. Endo ◽  
T. Onaya
Keyword(s):  
Ligand Binding ◽  
Thyrotropin Receptor ◽  
Extracellular Loop

Thyrotropin receptor activation by autoantibodies: A butterfly effect

2011 ◽  
Vol 72 (2) ◽  
pp. 114-116
Author(s):  
S. Costagliola
Keyword(s):  
Receptor Activation ◽  
Thyrotropin Receptor ◽  
Butterfly Effect

scholarly journals Three “hotspots” important for adenosine A2B receptor activation: a mutational analysis of transmembrane domains 4 and 5 and the second extracellular loop

2011 ◽  
Vol 8 (1) ◽  
pp. 23-38 ◽  
Author(s):  
Miriam C. Peeters ◽  
Qilan Li ◽  
Gerard J. P. van Westen ◽  
Ad P. IJzerman
Keyword(s):  
Mutational Analysis ◽  
Receptor Activation ◽  
Transmembrane Domains ◽  
Extracellular Loop ◽  
Adenosine A2b Receptor ◽  
A2b Receptor ◽  
Adenosine A2b

scholarly journals Changes to Gonadotropin-Releasing Hormone (GnRH) Receptor Extracellular Loops Differentially Affect GnRH Analog Binding and Activation: Evidence for Distinct Ligand-Stabilized Receptor Conformations

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 3118-3129 ◽  
Author(s):  
Kevin D. G. Pfleger ◽  
Adam J. Pawson ◽  
Robert P. Millar
Keyword(s):  
Ligand Binding ◽  
Receptor Activation ◽  
Gnrh Receptor ◽  
Binding Modes ◽  
Extracellular Loop ◽  
Gnrh Analog ◽  
Chimeric Receptors ◽  
Gnrh Receptors ◽  
Extracellular Loops ◽  
Loop Conformation

GnRH and its structural variants bind to GnRH receptors from different species with different affinities and specificities. By investigating chimeric receptors that combine regions of mammalian and nonmammalian GnRH receptors, a greater understanding of how different domains influence ligand binding and receptor activation can be achieved. Using human-catfish and human-chicken chimeric receptors, we demonstrate the importance of extracellular loop conformation for ligand binding and agonist potency, providing further evidence for GnRH and GnRH II stabilization of distinct active receptor conformations. We demonstrate examples of GnRH receptor gain-of-function mutations that apparently improve agonist potency independently of affinity, implicating a role for extracellular loops in stabilizing the inactive receptor conformation. We also show that entire extracellular loop substitution can overcome the detrimental effects of localized mutations, thereby demonstrating the importance of considering the conformation of entire domains when drawing conclusions from point-mutation studies. Finally, we present evidence implicating the configuration of extracellular loops 2 and 3 in combination differentiating GnRH analog binding modes. Because there are two endogenous forms of GnRH ligand but only one functional form of full-length GnRH receptor in humans, understanding how GnRH and GnRH II can elicit distinct functional effects through the same receptor is likely to provide important insights into how these ligands can have differential effects in both physiological and pathological situations.

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

2005 ◽  
Vol 152 (4) ◽  
pp. 625-634 ◽  
Author(s):  
Susanne Neumann ◽  
Maren Claus ◽  
Ralf Paschke
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Inositol Phosphate ◽  
Extracellular Domain ◽  
Receptor Activation ◽  
Tsh Receptor ◽  
Constitutive Activity ◽  
Extracellular Loops ◽  
Activating Mutation

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.

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