Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer

• Published in: The Journal of biological chemistry Vol. 289; no. 20; pp. 14273 - 14282
• Main Authors: Jiang, Xuliang, Fischer, David, Chen, Xiaoyan, McKenna, Sean D., Liu, Heli, Sriraman, Venkataraman, Yu, Henry N., Goutopoulos, Andreas, Arkinstall, Steve, He, Xiaolin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-05-2014; American Society for Biochemistry and Molecular Biology
• Subjects: Allosteric Regulation; Animals; Arrestin; CHO Cells; Cricetinae; Cricetulus; Cysteine-knot Growth Factor; Follicle Stimulating Hormone - metabolism; G Protein-coupled Receptors (GPCR); Glycoprotein Hormones; Humans; Intracellular Space - metabolism; Models, Molecular; Mutagenesis; Mutation; Protein Multimerization; Protein Structure, Quaternary; Receptor Structure-function; Receptors, FSH - agonists; Receptors, FSH - antagonists & inhibitors; Receptors, FSH - chemistry; Receptors, FSH - metabolism; Reproduction; Signal Transduction; G Protein-coupled Receptors (GPCR); Reproduction; Allosteric Regulation; Arrestin; Cysteine-knot Growth Factor; Receptor Structure-function; Glycoprotein Hormones
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.549592

Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor, is an important drug target in the development of 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.
A carbohydrate of follicle-stimulating hormone (FSH) has been proposed to sterically block other FSH molecules from binding to the putative receptor (FSHR) trimer.
FSH increases its receptor binding by 3-fold when the steric hindrance is removed.
FSHR forms a functional trimer.
This knowledge may improve designs of therapeutic drugs targeting FSHR.