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The Postendocytotic Trafficking of the Human Lutropin Receptor Is Mediated by a Transferable Motif Consisting of the C-Terminal Cysteine and an Upstream Leucine

Department of Pharmacology, The University of Iowa, Iowa City, Iowa 52242-1109

Address all correspondence and requests for reprints to: Dr. Mario Ascoli, Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, 2-319B BSB, 51 Newton Road, Iowa City, Iowa 52242-1109. E-mail: mario-ascoli{at}uiowa.edu.

Mutants of the human (h) lutropin receptor (LHR) were analyzed using a combination of biochemical and imaging approaches to define motifs that participate in the postendocytotic sorting of this G protein-coupled receptor (GPCR).

We show that a substantial portion of the human chorionic gonadotropin internalized by the hLHR sorts to a recycling pathway, and the internalized hLHR accumulates in endosomes because of the C-terminal cysteine (Cys⁶⁹⁹) and an upstream Leu⁶⁸³ present in the hLHR. The removal or simultaneous mutation of these two residues reroutes the internalized human chorionic gonadotropin to a degradation pathway and the internalized hLHR to lysosomes. We also show that grafting the 17 C-terminal residues of the hLHR into the C-terminal tail of two GPCRs that are routed to a lysosomal/degradation pathway (the rat LHR or the murine opioid receptor) reroutes them to an endosomal/recycling pathway. This is due to the Leu⁶⁸³ and Cys⁶⁹⁹ combination and another recycling motif (Gly⁶⁸⁷Thr⁶⁸⁸) that was previously identified in the hLHR. The importance of both motifs can be readily ascertained in the context of a murine opioid receptor/hLHR chimera. The importance of the Gly⁶⁸⁷Thr⁶⁸⁸ motif is revealed mostly in the context of a rat LHR/hLHR chimera.

These studies define a novel, noncontiguous, transferable motif that participates in the sorting of internalized GPCRs.

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