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Submitted on April 10, 2003
Accepted on December 17, 2003
1 INSERM E120, Bâtiment Grégory Pincus and Laboratoire d'Hormonologie et Biologie Moléculaire Hôpital de Bicêtre, IFR 93, 80, rue du Général Leclerc 94275 Le Kremlin Bicêtre, France. UMR 8125 CNRS Institut Gustave Roussy - PR1, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. CNRS UMR 6014, Université de Rouen, 76821 Mont Saint Aignan, France. INSERM U 413, Université de Rouen, 76821 Mont Saint Aignan, France.
* To whom correspondence should be addressed. E-mail: micheline.misrahi{at}bct.ap-hop-paris.fr.
The mechanisms of the basolateral targeting of G protein-coupled receptors remain largely unknown. Mutagenesis experiments have allowed us to identify the basolateral sorting signals of the thyrotropin and LH receptors expressed in Madin-Darby Canine Kidney cells and thyroid follicular FRT cells. Unexpectedly these signals (amino acids 731-746 and 672-689 respectively) share an unusual localization in the distal part of the intracellular domain of the receptors, at a marked distance from the membrane. When grafted onto the p75-neurotrophin receptor, these signals redirect this normally apically expressed protein to the basolateral cell surface. They are independent of the endocytosis signal. The basolateral sorting signals of thyrotropin, LH and FSH receptors do not exhibit primary sequence homology with each other or with any other known signals. Furthermore circular dichroism studies show that the three signals exhibit distinct secondary structures. TSHR has a stable helical structure, LHR has both helix and 
-sheet structures and FSHR sorting signal has a main random coil structure.
This means that even in closely-related receptors different secondary structures can be found for basolateral signals unrelated to internalization signals. This observation contrasts to what is known about basolateral signals related to internalization signals for which a common -turn structure has been described.
Deletion of the basolateral sorting signals results in apical targeting of the receptors suggesting the existence of apical sorting information. However a soluble form of the thyrotropin receptor, which harbors all N- and putative O-linked oligosaccharides, is secreted in a non-polarized fashion. This implies that apical sorting information must be located elsewhere, either in the transmembrane or in the intracellular domains of the receptor.
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