Assembly and structural characterization of an authentic complex between human follicle stimulating hormone and a hormone-binding ectodomain of its receptor.
Follicle stimulating hormone (FSH) is secreted from the pituitary gland to regulate reproduction in vertebrates. FSH signals through a G-protein coupled receptor (FSHR) on the target cell surface. We describe here the strategy to produce a soluble FSH-FSHR complex that involves the co-secretion of a truncated FSHR ectodomain (FSHR(HB)) and a covalently linked FSHalphabeta heterodimer from baculovirus-infected insect cells. FSH binds to FSHR(HB) with a high affinity comparable to that for the full-length receptor. The crystal structure of the FSH-FSHR(HB) complex provides explanations for the high affinity and specificity of FSH interaction with FSHR, and it shows an unexpected dimerization of these complexes. Here we also compare the crystal structure with theoretical models of the FSH-FSHR-binding mode. We conclude that the FSH-FSHR(HB) structure gives an authentic representation of FSH binding to intact FSHR.
Fan
Qing R
QR
Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, NY 10032, United States.
Hendrickson
Wayne A
WA
D000818:Animals; D016367:Baculoviridae; D006063:Chorionic Gonadotropin / Q000737:chemistry; D002850:Chromatography, Gel; D003460:Crystallization; D019281:Dimerization; D037201:Follicle Stimulating Hormone, beta Subunit / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D015292:Glycoprotein Hormones, alpha Subunit / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011962:Receptors, FSH / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship
D006063:Chorionic Gonadotropin; D037201:Follicle Stimulating Hormone, beta Subunit; D015292:Glycoprotein Hormones, alpha Subunit; D011962:Receptors, FSH