Anterograde trafficking of G protein-coupled receptors: function of the C-terminal F(X)6LL motif in export from the endoplasmic reticulum.

Molecular Pharmacology
Matthew T DuvernayGuangyu Wu

Abstract

We have reported previously that the F(X)(6)LL motif in the C termini is essential for export of alpha(2B)-adrenergic (alpha(2B)-AR) and angiotensin II type 1 receptors (AT1Rs) from the endoplasmic reticulum (ER). Here, we further demonstrate that mutation of the F(X)(6)LL motif similarly abolished the cell-surface expression of alpha(2B)-AR, AT1R, alpha(1B)-AR, and beta(2)-AR, suggesting that the F(X)(6)LL motif plays a general role in ER export of G protein-coupled receptors (GPCRs). Mutation of Phe to Val, Leu, Trp, and Tyr, and mutation of LL to FF and VV, markedly inhibited alpha(2B)-AR transport, indicating that the F(X)(6)LL function cannot be fully substituted by other hydrophobic residues. The structural analysis revealed that the Phe residue in the F(X)(6)LL motif is buried in the transmembrane domains and possibly interacts with Ile58 in beta(2)-AR and Val42 in alpha(2B)-AR, whereas the LL motif is exposed to the cytosolic space. Indeed, mutation of Ile58 in beta(2)-AR and Val42 in alpha(2B)-AR markedly disrupted cell surface transport of the receptors. It is noteworthy that the Val and Ile residues are highly conserved among the GPCRs carrying the F(X)(6)LL motif. Furthermore, the Phe mutant exhibited a stronger int...Continue Reading

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Citations

Jul 17, 2013·Best Practice & Research. Clinical Endocrinology & Metabolism·Gerda E Breitwieser
Oct 30, 2012·The Journal of Biological Chemistry·Chunman LiGuangyu Wu
Aug 24, 2013·The Journal of Biological Chemistry·Christian BergmayrChristian W Gruber
Oct 21, 2009·The Journal of Pharmacology and Experimental Therapeutics·Gregory W SawyerCrystal A Shults
Jan 23, 2010·The Journal of Pharmacology and Experimental Therapeutics·Chunmin DongGuangyu Wu
Jan 24, 2014·Molecular Biology of the Cell·Hirendrasinh B ParmarRoy Duncan
May 16, 2012·Cellular Signalling·Cathleen JuhlAnnette G Beck-Sickinger
Sep 8, 2009·Trends in Biochemical Sciences·Danijela Markovic, Dimitris K Grammatopoulos
May 10, 2013·Journal of Neuropathology and Experimental Neurology·Paula Garcia-EsparciaIsidre Ferrer
Jan 20, 2011·Journal of Neurochemistry·Rebecca StadelDebra A Kendall
May 19, 2010·Biochimica Et Biophysica Acta·Simon KeuerleberMichael Freissmuth
Jul 28, 2016·Frontiers in Aging Neuroscience·Isidro FerrerStefano Gustincich
Oct 24, 2009·Current Opinion in Pharmacology·Graeme Milligan
Mar 12, 2010·Molecular Pharmacology·Laura Málaga-DiéguezChristian Nanoff
Jan 20, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Matthias KotthoffDietmar Krautwurst
Sep 25, 2021·Journal of Neuroscience Research·Jade DegrandmaisonLouis Gendron

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