title: Distinct loops in arrestin differentially regulate ligand binding within the GPCR opsin.
abstract: G-protein-coupled receptors are universally regulated by arrestin binding. Here we show that rod arrestin induces uptake of the agonist all-trans-retinal [corrected] in only half the population of phosphorylated opsin in the native membrane. Agonist uptake blocks subsequent entry of the inverse agonist 11-cis-retinal (that is, regeneration of rhodopsin), but regeneration is not blocked in the other half of aporeceptors. Environmentally sensitive fluorophores attached to arrestin reported that conformational changes in loop(V-VI) (N-domain) are coupled to the entry of agonist, while loop(XVIII-XIX) (C-domain) engages the aporeceptor even before agonist is added. The data are most consistent with a model in which each domain of arrestin engages its own aporeceptor, and the different binding preferences of the domains lead to asymmetric ligand binding by the aporeceptors. Such a mechanism would protect the rod cell in bright light by concurrently sequestering toxic all-trans-retinal [corrected] and allowing regeneration with 11-cis-retinal.
authors.affiliation: Institut für Medizinische Physik und Biophysik (CC2), Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. martha.sommer@charite.de
authors.forename: Martha E
authors.initials: ME
authors.lastname: Sommer
authors.forename: Klaus Peter
authors.initials: KP
authors.lastname: Hofmann
authors.forename: Martin
authors.initials: M
authors.lastname: Heck
mesh_terms: D000818:Animals; D019393:Arrestin / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D008958:Models, Molecular; D008962:Models, Theoretical; D055355:Opsins / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012172:Retinaldehyde / Q000378:metabolism; D013050:Spectrometry, Fluorescence
chemical_list: D019393:Arrestin; D055355:Opsins; D012172:Retinaldehyde