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J. Biol. Chem., Vol. 279, Issue 43, 44438-44441, October 22, 2004

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Only a Portion of the Small Seatbelt Loop in Human Choriogonadotropin Appears Capable of Contacting the Lutropin Receptor^*

Michael P. Bernard, Win Lin, Donghui Cao, Rebecca V. Myers, Yongna Xing, and William R. Moyle

From the Department of OB-GYN, Robert Wood Johnson (Rutgers) Medical School, Piscataway, New Jersey 08854

Twenty residues of the human choriogonadotropin (hCG) -subunit that are wrapped around -subunit loop 2 like a "seatbelt" stabilize the heterodimer and enable the hormone to distinguish lutropin (LHR), follitropin, and thyrotropin receptors. The N-terminal portion of the seatbelt contains a small disulfide-stabilized loop needed for heterodimer assembly and is thought to mediate hCG-LHR interactions. To test the latter notion, we compared the LHR binding and signal transduction activities of hCG analogs in which the -subunit C terminus (CT) was cross-linked to residues in the small seatbelt loop. Analogs having an intersubunit disulfide between a cysteine in place of CT residue Ser-92 and cysteines substituted for loop residues Arg-94, Arg-95, or Ser-96 had high activities in LHR binding and signaling assays despite the fact that both portions of the hormone are thought to be essential for hCG activity. Use of a larger probe blocked hormone activity when the CT was cross-linked to cysteines in place of residues Arg-95 and Asp-99, but not to cysteines in place of residues Arg-94, Ser-96, or Thr-97. This suggested that the side chains of residues Arg-95 and Asp-99, which face in the same outward direction from the heterodimer, are nearer than the others to the LHR interface. The finding that residue 95 can be cross-linked to small CT probes without eliminating hormone activity indicates its side chain does not participate in essential LHR contacts. We suggest that contacts between the small seatbelt loop and the LHR, if any, involve its backbone atoms and possibly the side chain of residue Asp-99.

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

^* This work was supported by NICHD National Institutes of Health Grants HD14907 and HD28547. 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.

To whom correspondence should be addressed. Tel.: 732-235-4224; Fax: 732-235-4225; E-mail: moyle{at}umdnj.edu.

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