Evidence for follicle-stimulating hormone receptor as a functional trimer

Xuliang Jiang*, David Fischer, Xiaoyan Chen, Sean D. McKenna, Heli Liu, Venkataraman Sriraman, Henry N. Yu, Andreas Goutopoulos, Steve Arkinstall, Xiaolin He

*Corresponding author for this work

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor, is an important drug target in the developmentof novel therapeutics for reproductive indications. The FSHR extracellular domains were observed in the crystal structure as a trimer, which enabled us to propose a novel model for the receptor activation mechanism. The model predicts that FSHR binds Asnα52-deglycosylated FSH at a 3-fold higher capacity than fully glycosylated FSH. It also predicts that, upon dissociation of the FSHR trimer into monomers, the binding of glycosylated FSH, but not deglycosylated FSH, would increase 3-fold, and that the dissociated monomers would in turn enhance FSHR binding and signaling activities by 3-fold. This study presents evidence confirming these predictions and provides crystallographic and mutagenesis data supporting the proposed model. The model also provides a mechanistic explanation to the agonist and antagonist activities of thyroid-stimulating hormone receptor autoantibodies. We conclude that FSHR exists as a functional trimer.

Original languageEnglish (US)
Pages (from-to)14273-14282
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number20
DOIs
StatePublished - May 16 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Jiang, X., Fischer, D., Chen, X., McKenna, S. D., Liu, H., Sriraman, V., Yu, H. N., Goutopoulos, A., Arkinstall, S., & He, X. (2014). Evidence for follicle-stimulating hormone receptor as a functional trimer. Journal of Biological Chemistry, 289(20), 14273-14282. https://doi.org/10.1074/jbc.M114.549592