title: Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer.
abstract: 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 Asnα(52)-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.
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and xuliang.jiang@emdserono.com.
authors.forename: Xuliang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and.
authors.forename: David
authors.initials: D
authors.lastname: Fischer
authors.affiliation: the Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and.
authors.forename: Sean D
authors.initials: SD
authors.lastname: McKenna
authors.affiliation: the Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Heli
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Sriraman
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Yu
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Goutopoulos
authors.affiliation: From the EMD Serono Research and Development Institute, Billerica, Massachusetts 01821 and.
authors.forename: Steve
authors.initials: S
authors.lastname: Arkinstall
authors.affiliation: the Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: He
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008958:Models, Molecular; D016296:Mutagenesis; D009154:Mutation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011962:Receptors, FSH / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone
keywords: Allosteric Regulation; Arrestin; Cysteine-knot Growth Factor; G Protein-coupled Receptors (GPCR); Glycoprotein Hormones; Receptor Structure-function; Reproduction