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J. Biol. Chem., Vol. 279, Issue 49, 51590-51600, December 3, 2004

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Identification of a Novel Epitope in the Thyroid-stimulating Hormone Receptor Ectodomain Acting as Intramolecular Signaling Interface^*

Gunnar Kleinau, Holger Jäschke, Susanne Neumann¶, Jens Lättig, Ralf Paschke, and Gerd Krause||

From the Forschungsinstitut für Molekulare Pharmakologie, D-13125 Berlin, Germany, the III Department of Medicine, Universitätsklinikum Leipzig, D-04103 Leipzig, Germany, and ^¶NIDDK, National Institutes of Health, CEB, Bethesda, Maryland 20892

Glycoprotein hormone receptors (GPHRs) differ from the other seven transmembrane receptors mainly through a complex activation mechanism that requires the binding of a large hormone toward a large N-terminal ectodomain. The intramolecular mechanism of the signal transduction to the serpentine domain upon hormone binding at the ectodomain is not understood. To identify determinants at the GPHR ectodomain that may be involved in signal transduction, we first searched for homologous structural features. Based on high sequence similarity to the determined structures of the Nogo-receptor ectodomain and the intermolecular complex of the Interleukin-8 ligand (IL8) and the N-terminal peptide of the IL8 receptor (IL8RA), the hypothesis was developed that portions of the intramolecular components, Cysteine-box-2 and Cysteine-box-3, of the GPHR ectodomain interact and localize at the interface between ectodomain and serpentine domain. Indeed, point mutations within the D⁴⁰³EFN⁴⁰⁶ motif at Cysteine-box-3 of the thyrotropin receptor resulted in increased basal cAMP levels, suggesting that this motif may be important for transduction of the signal from the ectodomain to the transmembrane domain. New indications are provided about the tight spatial cooperation and relative location of the new epitope and other determinants at the thyrotropin receptor ectodomain, such as the leucine-rich repeat motif Ser²⁸¹ and the cysteine boxes. According to the high sequence conservation, the results are of general relevance for the signal transduction mechanism of other glycoprotein hormone receptors such as choriogonadotrophic/luteinizing hormone receptor and follicle-stimulating hormone receptor.

Received for publication, April 28, 2004 , and in revised form, September 1, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft (PA 423/12-1 and KR 1273/1-1), the Bundesministerium für Bildung und Forschung, and the Interdisciplinary Center for Clinical Research (IZKF) at the University of Leipzig (project B19). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplementary figures.

^|| To whom correspondence should be addressed: Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Str.10, D-13125 Berlin, Germany. Tel.: 49-30-94793228; Fax: 49-30-94793230; E-mail: GKrause{at}FMP-Berlin.de.

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