The biologic action of single-chain choriogonadotropin is not dependent on the individual disulfide bonds of the β subunit

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

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Disrupting disulfide loops in the human chorionic gonadotropin β subunit (CGβ) inhibits combination with the α 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 CGβ subunits bearing paired cysteine mutations to a wild-type α (WTα) subunit. The changes altered secretion of the single-chain mutants which parallel that seen for the CGβ 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.

Original languageEnglish
Pages (from-to)6827-6830
Number of pages4
JournalJournal of Biological Chemistry
Volume272
Issue number11
DOIs
StatePublished - Mar 14 1997

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