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Volume 272, Number 11, Issue of March 14, 1997 pp. 6827-6830
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
The Biologic Action of Single-chain Choriogonadotropin Is Not Dependent on the Individual Disulfide Bonds of the beta  Subunit

(Received for publication, November 7, 1996, and in revised form, January 10, 1997)

David Ben-Menahem , Masataka Kudo § , Mary R. Pixley , Asomi Sato , Nobuhiko Suganuma , Emerald Perlas § , Aaron J. W. Hsueh § and Irving Boime

From the Department of Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110 and the § Division of Reproductive Biology, Department of Gynecology/Obstetrics, Stanford University Medical Center, Stanford, California 94305-5317

Disrupting disulfide loops in the human chorionic gonadotropin beta  subunit (CGbeta ) inhibits combination with the alpha  subunit. Because the bioactivity requires a heterodimer, studies on the role of disulfide bonds on receptor binding/signal transduction have previously been precluded. To address this problem, we bypassed the assembly step and genetically fused CGbeta subunits bearing paired cysteine mutations to a wild-type alpha  (WTalpha ) subunit. The changes altered secretion of the single-chain mutants which parallel that seen for the CGbeta monomeric subunit. Despite conformational changes in CG disulfide bond mutants (assayed by gel electrophoresis and conformationally sensitive monoclonal antibodies), the variants bind to the lutropin/CG receptor and activated adenylate cyclase in vitro. The data show that the structural requirements for secretion and bioactivity are not the same. The results also suggest that the extensive native subunit interactions determined by the cystine bonds are not required for signal transduction. Moreover, these studies demonstrate that the single-chain model is an effective approach to structure-activity relationships of residues and structural domains associated with assembly of multisubunit ligands.


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