Expression of biologically active fusion genes encoding the common or subunit and either the CGβ or FSHβ subunits: Role of a linker sequence

Tadashi Sugahara, Peter D.J. Grootenhuis, Asomi Sato, Masataka Kudo, David Ben-Menahem, Mary R. Pixley, Aaron J.W. Hsueh, Irving Boime

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The gonadotropin/thyrotropin hormone family is characterized by a heterodimeric structure composed of a common α subunit non-covalently linked to a hormone-specific β subunit. The conformation of the heterodimer is essential for controlling secretion, hormone-specific post-translational modifications and signal transduction. Structure-function studies of FSH and the other glycoprotein hormones are often hampered by mutagenesis induced defects in subunit combination. Thus, the ability to overcome the limitation of subunit assembly would expand the range of structure activity relationships that can be performed on these hormones. Here we converted the FSH heterodimer to a single chain by genetically fusing the carboxyl end of the FSHβ subunit to the amino end of the α subunit in the presence or absence of a natural linker sequence. In the absence of the CTP linker, the secretion rate was decreased over three fold. (The CTP sequence is the last 28 amino acids of the CGβ sequence and contains four serine-linked oligosaccharides). Unexpectedly however, receptor binding/signal transduction was unaffected by absence of the linker. Molecular modelling of the tethers lacking the linker sequence show that the alignment of the α/β domains in the single chain differ substantially from that seen in the heterodimer. These data show that the single chain FSH was secreted efficiently and is biologically active and that the conformation determinants required for secretion and biologic activity are not the same.

Original languageEnglish
Pages (from-to)71-77
Number of pages7
JournalMolecular and Cellular Endocrinology
Volume125
Issue number1-2
DOIs
StatePublished - Dec 20 1996

Keywords

  • Biologic activity
  • Structure-function
  • Tethered gonadotropins

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