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Submitted on July 24, 2003
Accepted on October 27, 2003
1 Department of Pharmacology, The University of Iowa, Iowa City, Iowa 52242-1109
* To whom correspondence should be addressed. E-mail: mario-ascoli{at}uiowa.edu.
Mutants of the human lutropin receptor (hLHR) were analyzed using a combination of biochemical and imaging approaches to define motifs that participate in the post-endocytotic sorting of this G protein-coupled receptor (GPCR).
We show that a substantial portion of the hCG 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 Leu 683 present in the hLHR. The removal or simultaneous mutation of these two residues reroutes the internalized hCG 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, rLHR, or the murine delta opioid receptor mDOR) reroutes them to an endosomal/recycling pathway. This is due to the Leu 683/Cys699 combination and another recycling motif (Gly687Thr688) that was previously identified in the hLHR (Galet, C., Min, L., Narayanan, R., Kishi, M., Weigel, N. L., and Ascoli, M., Mol. Endocrinol. 17: 411-422, 2003). The importance of both motifs can be readily ascertained in the context of a mDOR/hLHR chimera. The importance of the Gly687Thr688 motif is revealed mostly in the context of a rLHR/hLHR chimera.
These studies define a novel, non-contiguous, transferable motif that participates in the sorting of internalized GPCRs.
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