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J. Biol. Chem., Vol. 279, Issue 29, 30741-30750, July 16, 2004

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A Conserved Motif for the Transport of G Protein-coupled Receptors from the Endoplasmic Reticulum to the Cell Surface^*

Matthew T. Duvernay, Fuguo Zhou, and Guangyu Wu

From the Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

The structural determinants for the export trafficking of G protein-coupled receptors are poorly defined. In this report, we determined the role of carboxyl termini (CTs) of _2B-adrenergic receptor (AR) and angiotensin II type 1A receptor (AT1R) in their transport from the endoplasmic reticulum (ER) to the cell surface. The _2B-AR and AT1R mutants lacking the CTs were completely unable to transport to the cell surface and were trapped in the ER. Alanine-scanning mutagenesis revealed that residues Phe⁴³⁶ and Ile⁴⁴³-Leu⁴⁴⁴ in the CT were required for _2B-AR export. Insertion or deletion between Phe⁴³⁶ and Ile⁴⁴³-Leu⁴⁴⁴ as well as Ile⁴⁴³-Leu⁴⁴⁴ mutation to FF severely disrupted _2B-AR transport, indicating there is a defined spatial requirement, which is essential for their function as a single motif regulating receptor transport from the ER. Furthermore, the carboxyl-terminally truncated as well as Phe⁴³⁶ and Ile⁴⁴³-Leu⁴⁴⁴ mutants were unable to bind ligand and the _2B-AR CT conferred its transport properties to the AT1R mutant without the CT in a Phe⁴³⁶-Ile⁴⁴³-Leu⁴⁴⁴-dependent manner. These data suggest that the Phe⁴³⁶ and Ile⁴⁴³-Leu⁴⁴⁴ may be involved in both proper folding and export from the ER of the receptor. Similarly, residues Phe³⁰⁹ and Leu³¹⁶-Leu³¹⁷ in the CT were identified as essential for AT1R export. The sequence F(X)₆LL (where X can be any residue, and L is leucine or isoleucine) is highly conserved in the membrane-proximal CTs of many G protein-coupled receptors and may function as a common motif mediating receptor transport from the ER to the cell surface.

Received for publication, December 18, 2003 , and in revised form, April 28, 2004.

^* This work was supported by National Institutes of Health Grant 1P20RR018766 and Louisiana Board of Regents Grant LEQSF (2002-05)-RD-A-18 (to G. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112. Tel.: 504-568-2236; Fax: 504-568-2361; E-mail: gwu{at}lsuhsc.edu.

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