| Structural highlights
4mqw is a 9 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| NonStd Res: | |
| Related: | 4ay9 |
| Gene: | CGA (HUMAN), FSHB (HUMAN), FSHR, LGR1 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[FSHR_HUMAN] Defects in FSHR are a cause of ovarian dysgenesis type 1 (ODG1) [MIM:233300]; also known as premature ovarian failure or gonadal dysgenesis XX type or XX gonadal dysgenesis (XXGD) or hereditary hypergonadotropic ovarian failure or hypergonadotropic ovarian dysgenesis with normal karyotype. ODG1 is an autosomal recessive disease characterized by primary amenorrhea, variable development of secondary sex characteristics, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).[1] [2] [3] [4] [5] [6] [7] Defects in FSHR are a cause of ovarian hyperstimulation syndrome (OHSS) [MIM:608115]. OHSS is a disorder which occurs either spontaneously or most often as an iatrogenic complication of ovarian stimulation treatments for in vitro fertilization. The clinical manifestations vary from abdominal distention and discomfort to potentially life-threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Pathologic features of this syndrome include the presence of multiple serous and hemorrhagic follicular cysts lined by luteinized cells, a condition called hyperreactio luteinalis.[8] [9] [10] [11] [12] [FSHB_HUMAN] Defects in FSHB are a cause of isolated follicle-stimulating hormone deficiency (IFSHD) [MIM:229070]. Selective follicle-stimulating hormone deficiency is an uncommon cause of infertility, producing amenorrhea and hypogonadism in women and oligo or azoospermia with normal testosterone levels in normally virilised men.[13] [14] [15]
Function
[FSHR_HUMAN] Receptor for follicle-stimulating hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. [FSHB_HUMAN] Stimulates development of follicle and spermatogenesis in the reproductive organs.
Publication Abstract from PubMed
Follicle stimulating hormone receptor (FSHR), a G-protein coupled receptor (GPCR), is an important drug target in the development of novel therapeutics for reproductive indications. The FSHR extracellular domains are 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 N52alpha-deglycosylated FSH at a three-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 three-fold, and that the dissociated monomers would in turn enhance FSHR binding and signaling activities by three-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 (TSHR) autoantibodies. We conclude that FSHR exists as a functional trimer.
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. 2014 Apr 2. PMID:24692546[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehvaslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995 Sep 22;82(6):959-68. PMID:7553856
- ↑ Jiang M, Aittomaki K, Nilsson C, Pakarinen P, Iitia A, Torresani T, Simonsen H, Goh V, Pettersson K, de la Chapelle A, Huhtaniemi I. The frequency of an inactivating point mutation (566C-->T) of the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybridization and time-resolved fluorometry. J Clin Endocrinol Metab. 1998 Dec;83(12):4338-43. PMID:9851774
- ↑ Beau I, Touraine P, Meduri G, Gougeon A, Desroches A, Matuchansky C, Milgrom E, Kuttenn F, Misrahi M. A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. J Clin Invest. 1998 Oct 1;102(7):1352-9. PMID:9769327 doi:10.1172/JCI3795
- ↑ Touraine P, Beau I, Gougeon A, Meduri G, Desroches A, Pichard C, Detoeuf M, Paniel B, Prieur M, Zorn JR, Milgrom E, Kuttenn F, Misrahi M. New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype. Mol Endocrinol. 1999 Nov;13(11):1844-54. PMID:10551778
- ↑ Doherty E, Pakarinen P, Tiitinen A, Kiilavuori A, Huhtaniemi I, Forrest S, Aittomaki K. A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. J Clin Endocrinol Metab. 2002 Mar;87(3):1151-5. PMID:11889179
- ↑ Allen LA, Achermann JC, Pakarinen P, Kotlar TJ, Huhtaniemi IT, Jameson JL, Cheetham TD, Ball SG. A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics. Hum Reprod. 2003 Feb;18(2):251-6. PMID:12571157
- ↑ Meduri G, Touraine P, Beau I, Lahuna O, Desroches A, Vacher-Lavenu MC, Kuttenn F, Misrahi M. Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies. J Clin Endocrinol Metab. 2003 Aug;88(8):3491-8. PMID:12915623
- ↑ Vasseur C, Rodien P, Beau I, Desroches A, Gerard C, de Poncheville L, Chaplot S, Savagner F, Croue A, Mathieu E, Lahlou N, Descamps P, Misrahi M. A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. N Engl J Med. 2003 Aug 21;349(8):753-9. PMID:12930927 doi:http://dx.doi.org/10.1056/NEJMoa030065
- ↑ Smits G, Olatunbosun O, Delbaere A, Pierson R, Vassart G, Costagliola S. Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. N Engl J Med. 2003 Aug 21;349(8):760-6. PMID:12930928 doi:http://dx.doi.org/10.1056/NEJMoa030064
- ↑ Montanelli L, Delbaere A, Di Carlo C, Nappi C, Smits G, Vassart G, Costagliola S. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndrome. J Clin Endocrinol Metab. 2004 Apr;89(4):1255-8. PMID:15080154
- ↑ De Leener A, Montanelli L, Van Durme J, Chae H, Smits G, Vassart G, Costagliola S. Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology. J Clin Endocrinol Metab. 2006 Feb;91(2):555-62. Epub 2005 Nov 8. PMID:16278261 doi:jc.2005-1580
- ↑ De Leener A, Caltabiano G, Erkan S, Idil M, Vassart G, Pardo L, Costagliola S. Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome. Hum Mutat. 2008 Jan;29(1):91-8. PMID:17721928 doi:10.1002/humu.20604
- ↑ Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, Casagrande S, Tedeschini G, Benedetti A, Chatterjee VK. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993 Sep;5(1):83-6. PMID:8220432 doi:http://dx.doi.org/10.1038/ng0993-83
- ↑ Layman LC, Lee EJ, Peak DB, Namnoum AB, Vu KV, van Lingen BL, Gray MR, McDonough PG, Reindollar RH, Jameson JL. Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene. N Engl J Med. 1997 Aug 28;337(9):607-11. PMID:9271483 doi:10.1056/NEJM199708283370905
- ↑ Matthews C, Chatterjee VK. Isolated deficiency of follicle-stimulating hormone re-revisited. N Engl J Med. 1997 Aug 28;337(9):642. PMID:9280841 doi:10.1056/NEJM199708283370918
- ↑ Jiang X, Fischer D, Chen X, McKenna SD, Liu H, Sriraman V, Yu HN, Goutopoulos A, Arkinstall S, He X. Evidence for Follicle-stimulating Hormone Receptor as a Functional Trimer. J Biol Chem. 2014 Apr 2. PMID:24692546 doi:http://dx.doi.org/10.1074/jbc.M114.549592
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