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J. Biol. Chem., Vol. 278, Issue 48, 47868-47876, November 28, 2003

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Orientation of Follicle-stimulating Hormone (FSH) Subunits Complexed with the FSH Receptor

SUBUNIT TOWARD THE N TERMINUS OF EXODOMAIN AND SUBUNIT TO EXOLOOP 3^*

Johann Sohn, HyeSook Youn, MyoungKun Jeoung, YongBum Koo, ChongSeoung Yi, Inhae Ji, and Tae H. Ji

From the Departments of Chemistry and Biology, University of Kentucky, Lexington, Kentucky 40506-0055

Follicle-stimulating hormone (FSH) comprises an subunit and a subunit, whereas the FSH receptor consists of two halves with distinct functions: the N-terminal extracellular exodomain and C-terminal membrane-associated endodomain. FSH initially binds to exodomain, and the resulting FSH/exodomain complex modulates the endodomain and generates signal. However, it has been difficult to determine which subunit of FSH contacts the exodomain or endodomain and in what orientation FSH interacts with them. To address these crucial issues, the receptor was Ala-scanned and the hormone subunits were probed with photoaffinity labeling with receptor peptides corresponding to the N-terminal region of the exodomain and exoloop 3 of the endodomain. Our results show that both regions of the receptors are important for hormone binding and signal generation. In addition, the FSH subunit is specifically labeled with the N-terminal peptide, whereas the subunit is labeled with the exoloop 3 peptide. These contrasting results show that the FSH subunit is close to the N-terminal region and that the subunit is projected toward exoloop 3 in the endodomain. The results raise the fundamental question whether the subunit, common among the glycoprotein hormones, plays a major role in generating the hormone signal common to all glycoprotein hormones.

Received for publication, July 17, 2003 , and in revised form, September 3, 2003.

^* This work was supported by Grants DK-51469 and HD-18702 from the National Institutes of Health. 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.

Currently on leave from InJe University (GhimHe, Korea).

To whom correspondence should be addressed: Dept. of Chemistry, University of Kentucky, Lexington, KY 40506-0055. Tel.: 859-257-3163; Fax: 859-257-3229; E-mail: tji{at}uky.edu.

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