The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

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dc.contributor.authorFlanagan, Colleen A
dc.contributor.authorZhou, Wei
dc.contributor.authorChi, Ling
dc.contributor.authorYuen, Tony
dc.contributor.authorRodic, Vladimir
dc.contributor.authorRobertson, Derek
dc.contributor.authorJohnson, Melanie
dc.contributor.authorHolland, Pamela
dc.contributor.authorMillar, Robert P
dc.contributor.authorWeinstein, Harel
dc.contributor.authorMitchell, Rory
dc.contributor.authorSealfon, Stuart C
dc.date.accessioned2021-10-08T07:20:46Z
dc.date.available2021-10-08T07:20:46Z
dc.date.issued1999
dc.description.abstractStructural microdomains of G protein-coupled receptors (GPCRs) consist of spatially related side chains that mediate discrete functions. The conserved helix 2/helix 7 microdomain was identified because the gonadotropin-releasing hormone (GnRH) receptor appears to have interchanged the Asp(2.50) and Asn(7.49) residues which are conserved in transmembrane helices 2 and 7 of rhodopsin-like GPCRs. We now demonstrate that different side chains of this microdomain contribute specifically to receptor expression, heterotrimeric G protein-, and small G protein-mediated signaling. An Asn residue is required in position 2.50(87) for expression of the GnRH receptor at the cell surface, most likely through an interaction with the conserved Asn(1.50(53)) residue, which we also find is required for receptor expression. Most GPCRs require an Asp side chain at either the helix 2 or helix 7 locus of the microdomain for coupling to heterotrimeric G proteins, but the GnRH receptor has transferred the requirement for an acidic residue from helix 2 to 7. However, the presence of Asp at the helix 7 locus precludes small G protein-dependent coupling to phospholipase D. These results implicate specific components of the helix 2/helix 7 microdomain in receptor expression and in determining the ability of the receptor to adopt distinct activated conformations that are optimal for interaction with heterotrimeric and small G proteins.
dc.identifier.apacitationFlanagan, C. A., Zhou, W., Chi, L., Yuen, T., Rodic, V., Robertson, D., ... Sealfon, S. C. (1999). The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor. <i>The Journal of Biological Chemistry</i>, 274(41), 28880 - 28886. http://hdl.handle.net/11427/35000en_ZA
dc.identifier.chicagocitationFlanagan, Colleen A, Wei Zhou, Ling Chi, Tony Yuen, Vladimir Rodic, Derek Robertson, Melanie Johnson, et al "The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor." <i>The Journal of Biological Chemistry</i> 274, 41. (1999): 28880 - 28886. http://hdl.handle.net/11427/35000en_ZA
dc.identifier.citationFlanagan, C.A., Zhou, W., Chi, L., Yuen, T., Rodic, V., Robertson, D., Johnson, M. & Holland, P. et al. 1999. The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor. <i>The Journal of Biological Chemistry.</i> 274(41):28880 - 28886. http://hdl.handle.net/11427/35000en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - Flanagan, Colleen A AU - Zhou, Wei AU - Chi, Ling AU - Yuen, Tony AU - Rodic, Vladimir AU - Robertson, Derek AU - Johnson, Melanie AU - Holland, Pamela AU - Millar, Robert P AU - Weinstein, Harel AU - Mitchell, Rory AU - Sealfon, Stuart C AB - Structural microdomains of G protein-coupled receptors (GPCRs) consist of spatially related side chains that mediate discrete functions. The conserved helix 2/helix 7 microdomain was identified because the gonadotropin-releasing hormone (GnRH) receptor appears to have interchanged the Asp(2.50) and Asn(7.49) residues which are conserved in transmembrane helices 2 and 7 of rhodopsin-like GPCRs. We now demonstrate that different side chains of this microdomain contribute specifically to receptor expression, heterotrimeric G protein-, and small G protein-mediated signaling. An Asn residue is required in position 2.50(87) for expression of the GnRH receptor at the cell surface, most likely through an interaction with the conserved Asn(1.50(53)) residue, which we also find is required for receptor expression. Most GPCRs require an Asp side chain at either the helix 2 or helix 7 locus of the microdomain for coupling to heterotrimeric G proteins, but the GnRH receptor has transferred the requirement for an acidic residue from helix 2 to 7. However, the presence of Asp at the helix 7 locus precludes small G protein-dependent coupling to phospholipase D. These results implicate specific components of the helix 2/helix 7 microdomain in receptor expression and in determining the ability of the receptor to adopt distinct activated conformations that are optimal for interaction with heterotrimeric and small G proteins. DA - 1999 DB - OpenUCT DP - University of Cape Town IS - 41 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 1999 SM - 0021-9258 SM - 1083-351X T1 - The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor TI - The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor UR - http://hdl.handle.net/11427/35000 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35000
dc.identifier.vancouvercitationFlanagan CA, Zhou W, Chi L, Yuen T, Rodic V, Robertson D, et al. The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor. The Journal of Biological Chemistry. 1999;274(41):28880 - 28886. http://hdl.handle.net/11427/35000.en_ZA
dc.language.isoeng
dc.publisher.departmentDepartment of Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue41
dc.source.journalvolume274
dc.source.pagination28880 - 28886
dc.source.urihttps://dx.doi.org/10.1074/jbc.274.41.28880
dc.subject.otherAnimals
dc.subject.otherBinding, Competitive
dc.subject.otherCOS Cells
dc.subject.otherGTP-Binding Proteins
dc.subject.otherGlycerophospholipids
dc.subject.otherGonadotropin-Releasing Hormone
dc.subject.otherInositol Phosphates
dc.subject.otherMutation
dc.subject.otherPhospholipase D
dc.subject.otherProtein Binding
dc.subject.otherProtein Conformation
dc.subject.otherProtein Structure, Secondary
dc.subject.otherReceptors, LHRH
dc.subject.otherSignal Transduction
dc.subject.otherTransfection
dc.subject.otherType C Phospholipases
dc.titleThe Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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