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Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer.

Jiang X, Fischer D, Chen X, McKenna SD, Liu H, Sriraman V, Yu HN, Goutopoulos A, Arkinstall S, He X
J Biol Chem 289 14273-82 (2014)
Cited: 55 times
EuropePMC logo PMID: 24692546

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.

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  1. Production, purification, and characterization of recombinant hFSH glycoforms for functional studies. Butnev VY, Butnev VY, May JV, Shuai B, Tran P, White WK, Brown A, Smalter Hall A, Harvey DJ, Bousfield GR. Mol Cell Endocrinol 405 42-51 (2015)
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  3. In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f). Mastrangeli R, Satwekar A, Cutillo F, Ciampolillo C, Palinsky W, Longobardi S. PLoS One 12 e0184139 (2017)
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  5. Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival. Casarini L, Lazzaretti C, Paradiso E, Limoncella S, Riccetti L, Sperduti S, Melli B, Marcozzi S, Anzivino C, Sayers NS, Czapinski J, Brigante G, Potì F, La Marca A, De Pascali F, Reiter E, Falbo A, Daolio J, Villani MT, Lispi M, Orlando G, Klinger FG, Fanelli F, Rivero-Müller A, Hanyaloglu AC, Simoni M. iScience 23 101812 (2020)
  6. Crystal structure of LGR4-Rspo1 complex: insights into the divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (LGRs). Xu JG, Huang C, Yang Z, Jin M, Fu P, Zhang N, Luo J, Li D, Liu M, Zhou Y, Zhu Y. J Biol Chem 290 2455-2465 (2015)
  7. In Vitro Impact of FSH Glycosylation Variants on FSH Receptor-stimulated Signal Transduction and Functional Selectivity. Zariñán T, Butnev VY, Gutiérrez-Sagal R, Maravillas-Montero JL, Martínez-Luis I, Mejía-Domínguez NR, Juárez-Vega G, Bousfield GR, Ulloa-Aguirre A. J Endocr Soc 4 bvaa019 (2020)
  8. Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor. Sposini S, De Pascali F, Richardson R, Sayers NS, Perrais D, Yu HN, Palmer S, Nataraja S, Reiter E, Hanyaloglu AC. Front Pharmacol 11 593492 (2020)
  9. In Vitro Effects of the Endocrine Disruptor p,p'-DDT on Human Follitropin Receptor. Munier M, Grouleff J, Gourdin L, Fauchard M, Chantreau V, Henrion D, Coutant R, Schiøtt B, Chabbert M, Rodien P. Environ Health Perspect 124 991-999 (2016)
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  11. Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation. Schaarschmidt J, Nagel MBM, Huth S, Jaeschke H, Moretti R, Hintze V, von Bergen M, Kalkhof S, Meiler J, Paschke R. J Biol Chem 291 14095-14108 (2016)
  12. Evolution of specificity in cartilaginous fish glycoprotein hormones and receptors. Buechi HB, Bridgham JT. Gen Comp Endocrinol 246 309-320 (2017)
  13. Molecular characterization, expression profiles of the ovine FSHR gene and its association with litter size. Pan X, Liu S, Li F, Wang W, Li C, Ma Y, Li T. Mol Biol Rep 41 7749-7754 (2014)
  14. Crystal structure of a TSH receptor monoclonal antibody: insight into Graves' disease pathogenesis. Chen CR, Hubbard PA, Salazar LM, McLachlan SM, Murali R, Rapoport B. Mol Endocrinol 29 99-107 (2015)
  15. Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling. Agwuegbo UT, Colley E, Albert AP, Butnev VY, Bousfield GR, Jonas KC. Front Endocrinol (Lausanne) 12 765727 (2021)
  16. Discovery and Preclinical Development of Orally Active Small Molecules that Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism. Nataraja S, Yu H, Guner J, Palmer S. Front Pharmacol 11 602593 (2020)
  17. Pressuromodulation at the cell membrane as the basis for small molecule hormone and peptide regulation of cellular and nuclear function. Sarin H. J Transl Med 13 372 (2015)
  18. Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor. Duan J, Xu P, Zhang H, Luan X, Yang J, He X, Mao C, Shen DD, Ji Y, Cheng X, Jiang H, Jiang Y, Zhang S, Zhang Y, Xu HE. Nat Commun 14 519 (2023)
  19. Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation. Charmandari E, Guan R, Zhang M, Silveira LG, Fan QR, Chrousos GP, Sertedaki AC, Latronico AC, Segaloff DL. Mol Endocrinol 30 62-76 (2016)
  20. Trivalent ligands for CXCR4 bearing polyproline linkers show specific recognition for cells with increased CXCR4 expression. Nomura W, Koseki T, Ohashi N, Mizuguchi T, Tamamura H. Org Biomol Chem 13 8734-8739 (2015)
  21. Computational model of the full-length TSH receptor. Mezei M, Latif R, Davies TF. Elife 11 e81415 (2022)
  22. Structure of full-length TSH receptor in complex with antibody K1-70™. Núñez Miguel R, Sanders P, Allen L, Evans M, Holly M, Johnson W, Sullivan A, Sanders J, Furmaniak J, Rees Smith B. J Mol Endocrinol 70 e220120 (2023)
  23. A Novel Follitropin Analog Inhibits Follitropin Activity In Vitro. Azzam N, Bar-Shalom R, Fares F. Pharmaceutics 13 325 (2021)
  24. Human FSH Glycoform α-Subunit Asparagine52 Glycans: Major Glycan Structural Consistency, Minor Glycan Variation in Abundance. Butnev VY, May JV, Brown AR, Sharma T, Butnev VY, White WK, Harvey DJ, Bousfield GR. Front Endocrinol (Lausanne) 13 767661 (2022)
  25. Inadequate detection of the FSHR complicates future research on extragonadal FSHR localization. Tedjawirja VN, Hooijer GKJ, Savci-Heijink CD, Kovac K, Balm R, de Waard V. Front Endocrinol (Lausanne) 14 1095031 (2023)
  26. Oral follicle-stimulating hormone receptor agonist affects granulosa cells differently than recombinant human FSH. Guner JZ, Monsivais D, Yu H, Stossi F, Johnson HL, Gibbons WE, Matzuk MM, Palmer S. Fertil Steril 120 1061-1070 (2023)
  27. Structure of a Thyrotropin Receptor Monoclonal Antibody Variable Region Provides Insight into Potential Mechanisms for its Inverse Agonist Activity. Chen CR, McLachlan SM, Hubbard PA, McNally R, Murali R, Rapoport B. Thyroid 28 933-940 (2018)


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