Two transmembrane Cys residues are involved in 5-HT4 receptor dimerization
Autor: | Frank Lezoualc'h, Lucie Rivail, Sames Sicsic, Olivier Russo, Mohammed Akli Ayoub, Rodolphe Fischmeister, Alexandre Lucas, Isabelle Berque-Bestel, Ralf Jockers, Magali Berthouze |
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Přispěvatelé: | Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM) |
Rok vydání: | 2007 |
Předmět: |
Molecular model
Stereochemistry Dimer [SDV]Life Sciences [q-bio] Biophysics CHO Cells 7. Clean energy Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cricetulus Cricetinae Animals Humans Immunoprecipitation Point Mutation Macromolecular docking Amino Acid Sequence Cysteine Disulfides Receptor Molecular Biology ComputingMilieux_MISCELLANEOUS 030304 developmental biology G protein-coupled receptor 0303 health sciences Chemistry Cell Membrane Cell Biology Transmembrane protein 3. Good health Dithiothreitol Intramolecular force Luminescent Measurements Receptors Adrenergic beta-2 Receptors Serotonin 5-HT4 Dimerization 030217 neurology & neurosurgery |
Zdroj: | Biochemical and Biophysical Research Communications Biochemical and Biophysical Research Communications, Elsevier, 2007, 356 (3), pp.642-647. ⟨10.1016/j.bbrc.2007.03.030⟩ |
ISSN: | 0006-291X 1090-2104 |
DOI: | 10.1016/j.bbrc.2007.03.030⟩ |
Popis: | The 5-HT(4) receptor (5-HT(4)R) belongs to the G-protein-coupled receptor (GPCR) family and is of considerable interest for the development of new drugs to treat gastrointestinal diseases and memory disorders. The 5-HT(4)R exists as a constitutive dimer but its molecular determinants are still unknown. Using co-immunoprecipitation and Bioluminescence Resonance Energy Transfer (BRET) techniques, we show here that 5-HT(4)R homodimerization but not 5-HT(4)R-beta(2) adrenergic receptor (beta(2)AR) heterodimerization is largely decreased under reducing conditions suggesting the participation of disulfide bonds in 5-HT(4)R dimerization. Molecular modeling and protein docking experiments identified four cysteine (Cys) residues potentially involved in the dimer interface through intramolecular or intermolecular disulfide bonds. We show that disulfide bridges between Cys112 and Cys145 located within TM3 and TM4, respectively, are of critical importance for 5-HT(4)R dimer formation. Our data suggest that two disulfide bridges between two transmembrane Cys residues are involved in the dimerization interface of a GPCR. |
Databáze: | OpenAIRE |
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