Article ; Online: Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.
The Journal of biological chemistry
2016 Volume 291, Issue 29, Page(s) 15119–15130
Abstract: G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players ... widely in their requirement of the ECD for activation. In one group, represented by corticotrophin ... diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD ...
| Abstract | G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation. |
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| MeSH term(s) | Amino Acid Sequence ; Amino Acid Substitution ; Glucagon/metabolism ; Glucagon-Like Peptide 1/metabolism ; Glucagon-Like Peptide-1 Receptor/chemistry ; Glucagon-Like Peptide-1 Receptor/genetics ; Glucagon-Like Peptide-1 Receptor/metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Mutagenesis, Site-Directed ; Protein Domains ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/classification ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Glucagon/chemistry ; Receptors, Glucagon/genetics ; Receptors, Glucagon/metabolism ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Sequence Homology, Amino Acid ; Signal Transduction | |||||
| Chemical Substances | GLP1R protein, human ; Glucagon-Like Peptide-1 Receptor ; Receptors, G-Protein-Coupled ; Receptors, Glucagon ; Recombinant Fusion Proteins ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucagon (9007-92-5) | |||||
| Language | English | |||||
| Publishing date | 2016-05-13 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2997-x | |||||
| ISSN | 1083-351X ; 0021-9258 | |||||
| ISSN (online) | 1083-351X | |||||
| ISSN | 0021-9258 | |||||
| DOI | 10.1074/jbc.M116.726620 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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