Anterograde Trafficking of G Protein-Coupled Receptors: Function of the C-Terminal F(X)₆LL Motif in Export from the Endoplasmic Reticulum

Abstract

We have reported previously that the F(X) 6 LL motif in the C termini is essential for export of ␣ 2B -adrenergic (␣ 2B

Di-acidic Motifs in the Membrane-distal C Termini Modulate the Transport of Angiotensin II Receptors from the Endoplasmic Reticulum to the Cell Surface

“…These treatment conditions are known to promote the cell surface expression of certain misfolded proteins by virtue of either relaxing the quality control system or promoting tighter protein conformations within the ER. We have previously demonstrated that the residue Phe-436 modulates ␣ 2B -AR folding likely through intramolecular interactions with other hydrophobic residues such as Val-42 in the first transmembrane domain (25) and thus it was used as a positive control. HEK293 cells were transfected with ␣ 2B -AR, ␣ 2B -AR mutant F436A, AT2R, or AT2R mutant ExD-AxA and then either treated with DMSO, PD123319 or cultured at 30°C.…”

“…Similar to many other plasma membrane proteins, GPCR export from the ER is a key event in the anterograde trafficking to the cell surface (17)(18)(19)(20). Indeed, ER export has been shown to be a rate-limiting step for the cell surface transport of the receptors (21) and a number of studies have recently identified highly conserved hydrophobic sequences, which are required for GPCR export from the ER to the cell surface (22)(23)(24)(25)(26)(27). Although the molecular mechanism underlying the function of these motifs in controlling GPCR export remains elusive, several studies suggest that they are likely involved in the regulation of proper receptor folding in the ER.…”

“…First, these motifs are located in the 8 th ␣-helical region within the membrane-proximal C terminus which has been shown to interact with other intracellular domains. These intramolecular hydrophobic interactions may modulate proper receptor folding in the ER (25,28). Second, the defect in the transport of these motif mutants can be partially rescued by a number of treatments, such as pharmacologic chaperones, chemical chaperones and lowing temperature culture (20,25,27).…”

“…These intramolecular hydrophobic interactions may modulate proper receptor folding in the ER (25,28). Second, the defect in the transport of these motif mutants can be partially rescued by a number of treatments, such as pharmacologic chaperones, chemical chaperones and lowing temperature culture (20,25,27). Third, the receptor mutants have enhanced abilities to bind to chaperone proteins (25).…”

“…Second, the defect in the transport of these motif mutants can be partially rescued by a number of treatments, such as pharmacologic chaperones, chemical chaperones and lowing temperature culture (20,25,27). Third, the receptor mutants have enhanced abilities to bind to chaperone proteins (25). Fourth, none of these motifs have been shown to directly link to the COPII vesicles, which exclusively mediate the export of newly synthesized cargoes, including GPCRs, from the ER (29 -34).…”