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

39 Citations (Scopus)

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

Fingerprint

FSH Receptors
Monomers
Thyrotropin Receptors
Mutagenesis
G-Protein-Coupled Receptors
Autoantibodies
Crystal structure
Chemical activation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jiang, X., Fischer, D., Chen, X., McKenna, S. D., Liu, H., Sriraman, V., ... 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
Jiang, Xuliang ; Fischer, David ; Chen, Xiaoyan ; McKenna, Sean D. ; Liu, Heli ; Sriraman, Venkataraman ; Yu, Henry N. ; Goutopoulos, Andreas ; Arkinstall, Steve ; He, Xiaolin. / Evidence for follicle-stimulating hormone receptor as a functional trimer. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 20. pp. 14273-14282.
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Jiang, X, Fischer, D, Chen, X, McKenna, SD, Liu, H, Sriraman, V, Yu, HN, Goutopoulos, A, Arkinstall, S & He, X 2014, 'Evidence for follicle-stimulating hormone receptor as a functional trimer', Journal of Biological Chemistry, vol. 289, no. 20, pp. 14273-14282. https://doi.org/10.1074/jbc.M114.549592

Evidence for follicle-stimulating hormone receptor as a functional trimer. / Jiang, Xuliang; Fischer, David; Chen, Xiaoyan; McKenna, Sean D.; Liu, Heli; Sriraman, Venkataraman; Yu, Henry N.; Goutopoulos, Andreas; Arkinstall, Steve; He, Xiaolin.

In: Journal of Biological Chemistry, Vol. 289, No. 20, 16.05.2014, p. 14273-14282.

Research output: Contribution to journalArticle

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AU - Yu, Henry N.

AU - Goutopoulos, Andreas

AU - Arkinstall, Steve

AU - He, Xiaolin

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Jiang X, Fischer D, Chen X, McKenna SD, Liu H, Sriraman V et al. Evidence for follicle-stimulating hormone receptor as a functional trimer. Journal of Biological Chemistry. 2014 May 16;289(20):14273-14282. https://doi.org/10.1074/jbc.M114.549592