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J. Biol. Chem., Vol. 281, Issue 34, 24910-24921, August 25, 2006

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The Corticotropin-releasing Factor Receptor Type 2a Contains an N-terminal Pseudo Signal Peptide^*

Claudia Rutz¹, Armin Renner¹, Martina Alken, Katharina Schulz, Michael Beyermann, Burkhard Wiesner, Walter Rosenthal, and Ralf Schülein²

From the Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin and the Institut für Pharmakologie, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany

The corticotropin-releasing factor receptor type 2a (CRF_2(a) receptor) belongs to the family of G protein-coupled receptors. The receptor possesses a putative N-terminal signal peptide that is believed to be cleaved-off after mediating the endoplasmic reticulum targeting/insertion process, like the corresponding sequence of the homologous CRF₁ receptor. Here, we have assessed the functional significance of the putative signal peptide of the CRF_2(a) receptor and show that it is surprisingly completely incapable of mediating endoplasmic reticulum targeting, despite meeting all sequence criteria for a functional signal by prediction algorithms. Moreover, it is uncleaved and forms part of the mature receptor protein. Replacement of residue Asn¹³ by hydrophobic or positively charged residues converts the sequence into a fully functional and cleaved signal peptide demonstrating that conventional signal peptide functions are inhibited by a single amino acid residue. Deletion of the domain leads to an increase in the amount of immature, intracellularly retained receptors demonstrating that the sequence has adopted a new function in receptor trafficking through the early secretory pathway. Taken together, our results identify a novel hydrophobic receptor domain in the family of the heptahelical G protein-coupled receptors and the first pseudo signal peptide of a eukaryotic membrane protein. Our data also show that the extreme N termini of the individual CRF receptor subtypes differ substantially.

Received for publication, February 17, 2006 , and in revised form, May 15, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 449 and the Fonds der Chemischen Industrie. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany. Tel.: 49-30-94793-255; Fax: 49-30-94793-109; E-mail: schuelein{at}fmp-berlin.de.

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