Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor

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dc.contributor.authorBallesteros, Juan
dc.contributor.authorKitanovic, Smiljka
dc.contributor.authorGuarnieri, Frank
dc.contributor.authorDavies, Peter
dc.contributor.authorFromme, Bernard J
dc.contributor.authorKonvicka, Karel
dc.contributor.authorChi, Ling
dc.contributor.authorMillar, Robert P
dc.contributor.authorDavidson, James S
dc.contributor.authorWeinstein, Harel
dc.contributor.authorSealfon, Stuart C
dc.date.accessioned2021-10-08T07:20:45Z
dc.date.available2021-10-08T07:20:45Z
dc.date.issued1998
dc.description.abstractAn Arg present in the third transmembrane domain of all rhodopsin-like G-protein-coupled receptors is required for efficient signal transduction. Mutation of this Arg in the gonadotropin-releasing hormone receptor to Gln, His, or Lys abolished or severely impaired agonist-stimulated inositol phosphate generation, consistent with Arg having a role in receptor activation. To investigate the contribution of the surrounding structural domain in the actions of the conserved Arg, an integrated microdomain modeling and mutagenesis approach has been utilized. Two conserved residues that constrain the Arg side chain to a limited number of conformations have been identified. In the inactive wild-type receptor, the Arg side chain is proposed to form an ionic interaction with Asp3.49(138). Experimental results for the Asp3. 49(138) --> Asn mutant receptor show a modestly enhanced receptor efficiency, consistent with the hypothesis that weakening the Asp3. 49(138)-Arg3.50(139) interaction by protonation of the Asp or by the mutation to Asn favors activation. With activation, the Asp3. 49(138)-Arg3.50(139) ionic bond would break, and the unrestrained Arg would be prevented from orienting itself toward the water phase by a steric clash with Ile3.54(143). The mutation Ile3.54(143) --> Ala, which eliminates this clash in simulations, causes a marked reduction in measured receptor signaling efficiency, implying that solvation of Arg3.50(139) prevents it from functioning in the activation of the receptor. These data are consistent with residues Asp3.49(138) and Ile3.54(143) forming a structural motif, which helps position Arg in its appropriate inactive and active receptor conformations.
dc.identifier.apacitationBallesteros, J., Kitanovic, S., Guarnieri, F., Davies, P., Fromme, B. J., Konvicka, K., ... Sealfon, S. C. (1998). Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor. <i>The Journal of Biological Chemistry</i>, 273(17), 10445 - 10453. http://hdl.handle.net/11427/34999en_ZA
dc.identifier.chicagocitationBallesteros, Juan, Smiljka Kitanovic, Frank Guarnieri, Peter Davies, Bernard J Fromme, Karel Konvicka, Ling Chi, et al "Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor." <i>The Journal of Biological Chemistry</i> 273, 17. (1998): 10445 - 10453. http://hdl.handle.net/11427/34999en_ZA
dc.identifier.citationBallesteros, J., Kitanovic, S., Guarnieri, F., Davies, P., Fromme, B.J., Konvicka, K., Chi, L. & Millar, R.P. et al. 1998. Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor. <i>The Journal of Biological Chemistry.</i> 273(17):10445 - 10453. http://hdl.handle.net/11427/34999en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - Ballesteros, Juan AU - Kitanovic, Smiljka AU - Guarnieri, Frank AU - Davies, Peter AU - Fromme, Bernard J AU - Konvicka, Karel AU - Chi, Ling AU - Millar, Robert P AU - Davidson, James S AU - Weinstein, Harel AU - Sealfon, Stuart C AB - An Arg present in the third transmembrane domain of all rhodopsin-like G-protein-coupled receptors is required for efficient signal transduction. Mutation of this Arg in the gonadotropin-releasing hormone receptor to Gln, His, or Lys abolished or severely impaired agonist-stimulated inositol phosphate generation, consistent with Arg having a role in receptor activation. To investigate the contribution of the surrounding structural domain in the actions of the conserved Arg, an integrated microdomain modeling and mutagenesis approach has been utilized. Two conserved residues that constrain the Arg side chain to a limited number of conformations have been identified. In the inactive wild-type receptor, the Arg side chain is proposed to form an ionic interaction with Asp3.49(138). Experimental results for the Asp3. 49(138) --> Asn mutant receptor show a modestly enhanced receptor efficiency, consistent with the hypothesis that weakening the Asp3. 49(138)-Arg3.50(139) interaction by protonation of the Asp or by the mutation to Asn favors activation. With activation, the Asp3. 49(138)-Arg3.50(139) ionic bond would break, and the unrestrained Arg would be prevented from orienting itself toward the water phase by a steric clash with Ile3.54(143). The mutation Ile3.54(143) --> Ala, which eliminates this clash in simulations, causes a marked reduction in measured receptor signaling efficiency, implying that solvation of Arg3.50(139) prevents it from functioning in the activation of the receptor. These data are consistent with residues Asp3.49(138) and Ile3.54(143) forming a structural motif, which helps position Arg in its appropriate inactive and active receptor conformations. DA - 1998 DB - OpenUCT DP - University of Cape Town IS - 17 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 1998 SM - 0021-9258 SM - 1083-351X T1 - Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor TI - Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor UR - http://hdl.handle.net/11427/34999 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34999
dc.identifier.vancouvercitationBallesteros J, Kitanovic S, Guarnieri F, Davies P, Fromme BJ, Konvicka K, et al. Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor. The Journal of Biological Chemistry. 1998;273(17):10445 - 10453. http://hdl.handle.net/11427/34999.en_ZA
dc.language.isoeng
dc.publisher.departmentDivision of Chemical Pathology
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue17
dc.source.journalvolume273
dc.source.pagination10445 - 10453
dc.source.urihttps://dx.doi.org/10.1074/jbc.273.17.10445
dc.subject.otherAmino Acid Sequence
dc.subject.otherAmino Acid Substitution
dc.subject.otherAnimals
dc.subject.otherArginine
dc.subject.otherComputer Simulation
dc.subject.otherConserved Sequence
dc.subject.otherGTP-Binding Proteins
dc.subject.otherHumans
dc.subject.otherModels, Molecular
dc.subject.otherMolecular Sequence Data
dc.subject.otherReceptors, LHRH
dc.subject.otherReceptors, LHRH
dc.subject.otherArginine
dc.subject.otherGTP-Binding Proteins
dc.titleFunctional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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