Biosynthesis of a biologically active single peptide chain containing the human common α and chorionic gonadotropin β subunits in tandem

T. Sugahara, M. R. Pixley, S. Minami, E. Perlas, D. Ben-Menahem, A. J.W. Hsueh, I. Boime

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

One of the distinguishing features of the gonadotropin and thyrotropin hormone family is their heterodimeric structure, consisting of a common a subunit and a hormone-specific β subunit. Subunit assembly is vital to the function of these hormones: The conformation of the heterodimer is essential for controlling secretion, hormone-specific posttranslational modifications, and signal transduction. To address whether a and β subunits can be synthesized as one chain and also maintain biological activity, a chimera composed of the human chorionic gonadotropin (hCG) β subunit genetically fused to the a subunit was constructed. The resulting polypeptide hCG molecule not only was efficiently secreted but also displayed an increased biological activity in vitro and in vivo. These data show that the α and hCGβ subunits encoded as a single chain retain a biologically active conformation similar to that seen in the heterodimer. This approach can be used to investigate structure-function relationships of the glycoprotein hormone family that were previously not tractable because of the absolute dependence on assembly for the biological response. Moreover, other bioactive multisubunit ligands can be engineered where the combination efficiency and specificity of heterodimers and homodimers are otherwise difficult to control.

Original languageEnglish
Pages (from-to)2041-2045
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number6
DOIs
StatePublished - 1995

Keywords

  • single chain
  • structure-function analysis

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