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J. Biol. Chem., Vol. 279, Issue 43, 44442-44459, October 22, 2004

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Model of Glycoprotein Hormone Receptor Ligand Binding and Signaling^*

William R. Moyle, Yongna Xing, Win Lin, Donghui Cao, Rebecca V. Myers, John E. Kerrigan¶||, and Michael P. Bernard

From the Departments of OB-GYN and ^¶Academic Computing Services, Robert Wood Johnson (Rutgers) Medical School, Piscataway, New Jersey 08854

Studies described here were initiated to develop a model of glycoprotein hormone receptor structure and function. We found that the region that links the lutropin receptor leucine-rich repeat domain (LRD) to its transmembrane domain (TMD) has substantial roles in ligand binding and signaling, hence we term it the signaling specificity domain (SSD). Theoretical considerations indicated the short SSDs in marmoset lutropin and salmon follitropin receptors have KH domain folds. We assembled models of lutropin, follitropin, and thyrotropin receptors by aligning models of their LRD, TMD, and shortened SSD in a manner that explains how substitutions in follitropin and thyrotropin receptors distant from their apparent ligand binding sites enable them to recognize lutropins. In these models, the SSD is parallel to the concave surface of the LRD and makes extensive contacts with TMD outer loops 1 and 2. The LRD appears to contact TMD outer loop 3 and a few residues in helices 1, 5, 6, and 7. We propose that signaling results from contacts of the ligands with the SSD and LRD that alter the LRD, which then moves TMD helices 6 and 7. The positions of the LRD and SSD support the notion that the receptor can be activated by hormones that dock with these domains in either of two different orientations. This would account for the abilities of some ligands and ligand chimeras to bind multiple receptors and for some receptors to bind multiple ligands. This property of the receptor may have contributed significantly to ligand-receptor co-evolution.

Received for publication, June 22, 2004 , and in revised form, August 9, 2004.

^* This work was supported in part by National Institutes of Health Grants HD14907 and HD38547. 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.

^|| Supported by Academic Computing Services.

To whom correspondence should be addressed: Dept. of OB-GYN, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-4224; Fax: 732-235-4225; E-mail: moyle{at}umdnj.edu.

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