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 language | English (US) |
|---|---|
| Pages (from-to) | 14273-14282 |
| Number of pages | 10 |
| Journal | Journal of Biological Chemistry |
| Volume | 289 |
| Issue number | 20 |
| DOIs | |
| State | Published - May 16 2014 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
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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 journal › Article
TY - JOUR
T1 - Evidence for follicle-stimulating hormone receptor as a functional trimer
AU - Jiang, Xuliang
AU - Fischer, David
AU - Chen, Xiaoyan
AU - McKenna, Sean D.
AU - Liu, Heli
AU - Sriraman, Venkataraman
AU - Yu, Henry N.
AU - Goutopoulos, Andreas
AU - Arkinstall, Steve
AU - He, Xiaolin
PY - 2014/5/16
Y1 - 2014/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84901036055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901036055&partnerID=8YFLogxK
U2 - 10.1074/jbc.M114.549592
DO - 10.1074/jbc.M114.549592
M3 - Article
C2 - 24692546
AN - SCOPUS:84901036055
VL - 289
SP - 14273
EP - 14282
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 20
ER -