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The Basolateral Sorting Signals of the Thyrotropin and Luteinizing Hormone Receptors: An Unusual Family of Signals Sharing an Unusual Distal Intracellular Localization, but Unrelated in Their Structures

Institut National de la Santé et de la Recherche Médicale (INSERM), E120 (I.B., M.-T.G.P., A.D., J.-P.T., M.M.), and Laboratoire d’Hormonologie et Biologie Moléculaire Hôpital de Bicêtre, Institut Fédératif de Recherche 93 (M.M.), 94275 Le Kremlin Bicêtre, France; Unité Mixte de Recherche (UMR) 8125 Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy-PR1 (P.D.), 94805 Villejuif Cedex, France; CNRS, UMR 6014, Université de Rouen (E.C.), 76821 Mont Saint Aignan, France; and INSERM, Unité 413, Université de Rouen (J.L., H.V.), 76821 Mont Saint Aignan, France

Address all correspondence and requests for reprints to: Dr. Micheline Misrahi, Institut National de la Santé et de la Recherche Médicale E120, Bâtiment Grégory Pincus, 80 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.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 TSH 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-neurotropin 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 TSH, LH, and FSH receptors do not exhibit primary sequence homology with each other or with any other known signal. Furthermore, circular dichroism studies show that the three signals exhibit distinct secondary structures. The TSH receptor has a stable helical structure, the LH receptor has both helix and ß-sheet structures, and the FSH receptor 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 with what is known about basolateral signals related to internalization signals for which a common ß-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 TSH receptor, which harbors all N- and putative O-linked oligosaccharides, is secreted in a nonpolarized 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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