Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors.
J Biol Chem
; 292(24): 9865-9881, 2017 06 16.
Article
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| MEDLINE
| ID: mdl-28356352
ABSTRACT
The glucagon receptor (GCGR) belongs to the secretin-like (class B) family of G protein-coupled receptors (GPCRs) and is activated by the peptide hormone glucagon. The structures of an activated class B GPCR have remained unsolved, preventing a mechanistic understanding of how these receptors are activated. Using a combination of structural modeling and mutagenesis studies, we present here two modes of ligand-independent activation of GCGR. First, we identified a GCGR-specific hydrophobic lock comprising Met-338 and Phe-345 within the IC3 loop and transmembrane helix 6 (TM6) and found that this lock stabilizes the TM6 helix in the inactive conformation. Disruption of this hydrophobic lock led to constitutive G protein and arrestin signaling. Second, we discovered a polar core comprising conserved residues in TM2, TM3, TM6, and TM7, and mutations that disrupt this polar core led to constitutive GCGR activity. On the basis of these results, we propose a mechanistic model of GCGR activation in which TM6 is held in an inactive conformation by the conserved polar core and the hydrophobic lock. Mutations that disrupt these inhibitory elements allow TM6 to swing outward to adopt an active TM6 conformation similar to that of the canonical ß2-adrenergic receptor complexed with G protein and to that of rhodopsin complexed with arrestin. Importantly, mutations in the corresponding polar core of several other members of class B GPCRs, including PTH1R, PAC1R, VIP1R, and CRFR1, also induce constitutive G protein signaling, suggesting that the rearrangement of the polar core is a conserved mechanism for class B GPCR activation.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Modelos Moleculares
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Receptores de Glucagón
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Receptores de Hormona Liberadora de Corticotropina
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Receptor de Hormona Paratiroídea Tipo 1
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Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria
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Receptores de Tipo I del Polipéptido Intestinal Vasoactivo
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Biol Chem
Año:
2017
Tipo del documento:
Article
País de afiliación:
China