A Role for Glycosylation of the α Subunit in Transduction of Biological Signal in Glycoprotein Hormones

Sairam, M.R.; Bhargavi, G. N.

doi:10.1126/science.2990039

Cited by 220 publications

(79 citation statements)

References 17 publications

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“…It has been shown that gonadotropin isoforms influence a variety of biological activities, cellular growth and development, steroidogenesis and protein synthesis [37][38][39]. Because of their structural differences, FSH isoforms differ in their ability to bind to target cell receptors surviving in the circulation and induce a biological response in vivo and in vitro [40][41][42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of a combined protocol of urinary and recombinant follicle-stimulating hormone used for ovarian stimulation of patients undergoing ICSI cycle

Pacchiarotti

Aragona

Gaglione³

et al. 2007

J Assist Reprod Genet

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Purpose To evaluate the efficacy of using both urinary and recombinant FSH in a combined protocol for ovarian stimulation in an IVF treatment program. Method A total of 119 infertile couples undergoing ICSI treatment were randomized prospectively in this study. After a standard down-regulation with GnRH analogue, the patients were randomized in 2 groups 58 received combined urinary and recombinant FSH, starting with uFSH and then rFSH, and 61 controls received only recombinant FSH. Result(s) Pregnancy and implantation rates were significantly higher in the combined uFSH/rFSH group than the control (rFSH) group (43.9% vs 22.1% and 27.5% vs 13.2% respectively). Metaphase II oocyte and grade 1 embryos were significantly higher in favour of combined uFSH/rFSH group than the recombinant FSH group. Conclusion(s) This study shows that using a combination of both urinary and recombinant FSH for ovarian stimulation improves oocyte maturity and embryo cleavage, and increases pregnancy and implantation rates.

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Section: Discussionmentioning

confidence: 99%

Efficacy of a combined protocol of urinary and recombinant follicle-stimulating hormone used for ovarian stimulation of patients undergoing ICSI cycle

Pacchiarotti

Aragona

Gaglione³

et al. 2007

J Assist Reprod Genet

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“…Each subunit has two asparagine-linked (N-linked) oligosaccharides, attached at positions 52 and 78 on the -subunit and at positions 7 and 24 on the -subunit of human FSH (Baenzinger & Green 1988). These play a significant role in determining the plasma half-life, specific interaction with the target-cell receptor and capability of the hormone to activate one or more intracellular signal transduction pathways (Morell et al 1971, Sairam & Bhargavi 1985, Sairam 1989, Flack et al 1994b, Valove et al 1994, Arey et al 1997. In all glycoprotein hormones, the oligosaccharides are highly variable (Baenzinger & Green 1988).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of the charge variants of human follicle-stimulating hormone

Timossi¹,

Barrios-De-Tomasi²,

González-Suárez³

et al. 2000

Journal of Endocrinology

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FSH is synthesized and secreted by the anterior pituitary gland in multiple molecular forms; the release of these isoforms depends on the endocrine status of the donor at the time of sample collection. In the present study, we analysed the possibility that the FSH charge isoforms may exert differential effects at the target cell. Seven FSH isoform mixes were isolated from pooled anterior pituitary glycoprotein extracts by high resolution chromatofocusing, followed by affinity chromatography, which removed nearly 90% of the LH that co-eluted with the FSH isoforms during chromatofocusing. The isoforms (isoform I, pH >7·10; II, pH range 6·60-6·20; III, pH 5·47-5·10; IV, pH 5·03-4·60; V, pH 4·76-4·12; VI, pH 4·05-3·82 and VII, pH <3·80) were then tested for their capacity to stimulate cAMP release, androgen aromatization and tissue-type plasminogen activator (tPA) enzyme activity and cytochrome P450 aromatase, tPA and inhibin -subunit mRNA production by rat granulosa cells in culture. cAMP and oestradiol production were determined by RIA, tPA enzyme activity by SDS-PAGE and zymography and all mRNAs by northern blot hybridization analysis and semiquantitative RT-PCR. All isoforms, with the exception of isoform I, stimulated synthesis and release of cAMP, oestrogen and tPA enzyme activity in a dosedependent manner; the potency of the less acidic isoforms (pH 6·60-4·60) was greater than that exhibited by the more acidic/sialylated analogs (pH 4·76 to <3·80; potencies II>III>IV>V>VII>VI). A similar trend was observed in terms of cytochrome P450 aromatase and tPA mRNA production. In contrast, when FSH-stimulated production of -inhibin mRNA was analysed, isoforms V-VII were significantly more potent (two-to threefold) than the less acidic/sialylated counterparts (II-IV). In contrast to isoforms II-VII (which behaved as FSH agonists), isoform I (elution pH >7·10) completely blocked P450 aromatase and tPA mRNA expression, without altering that of a constitutively expressed gene (glyceraldehyde-3-phosphate dehydrogenase). These results show for the first time that the naturally occurring human FSH isoforms may exhibit differential or even unique effects at the target cell level.

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“…Deglycosylation of ahCG, by means of exoglycosidase digestion, chemical treatment or site-directed mutagenesis, enhances the reassociation rate with the / l subunit and leads to a higher affinity for the IutropinhCG receptor. However, the subsequent signal transduction is abolished, which leads to a drastic reduction of adenylate-cyclase activation and steroidogenic activity (Goverman et al, 1982: Kalyan andBahl, 1983;Keutmann et al, 1983;Sairam and Bhargavi, 1985;Matzuk et al, 1989;Sairam, 1989). Site-directed mutagenesis has revealed that the presence of an oligosaccharide at Am52 is essential for signal transduction .…”

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confidence: 99%

NMR Studies of the Free α Subunit of Human Chorionic Gonadotropin

Beer

Zuylen

Leeflang

et al. 1996

European Journal of Biochemistry

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Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone that is involved in the maintenance of the corpus luteum in early pregnancy. Glycosylation at Am52 of its a subunit (ahCG) is essential for signal transduction, whereas the N-glycan at Am78 stabilizes the structure of the protein.In this study, an almost complete 'H-NMR and a partial "C-NMR spectral assignment for the amino acids and the N-glycans of ahCG and of an enzymatically deglycosylated form, which had a single GlcNAc residue at each of its two glycosylation sites, has been achieved. The secondary structure of ahCG in solution, which was determined based on NOE data, is partially similar to that of the a subunit in the crystal structure of hCG, but large structural differences are found for amino acid residues 33-58.In the crystal structure of hCG, residues 33-37 and 54-58 of the a subunit are part of an intersubunit seven-stranded b-barrel and residues 41 -47 constitute a 3,,,-helix. In contrast, in free ahCG in solution, amino acids 33-58 are part of a large disordered loop, indicating that in intact hCG interactions with the /I subunit of hCG stabilize the conformation of the 0: subunit. The NMR data of ahCG and its deglycosylated counterpart are very similar, indicating that removal of carbohydrate residues other than GlcNAc-1 does not notably affect the conformation of the protein part. However, numerous 'H-NOES between the GlcNAc-1 residue at Am78 and several amino acid residues show that this GlcNAc residue is tightly packed against the protein, being an integral part of the structure of the IX subunit. 'H-NOES across the glycosidic linkages of the glycan, resonance-line widths, and 'H and I3C chemical shifts of the other monosaccharides suggest that the remainder of the glycans at Asn78, and the glycans at Asn.52 are largely extended in solution.

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A Role for Glycosylation of the α Subunit in Transduction of Biological Signal in Glycoprotein Hormones

Cited by 220 publications

References 17 publications

Efficacy of a combined protocol of urinary and recombinant follicle-stimulating hormone used for ovarian stimulation of patients undergoing ICSI cycle

Efficacy of a combined protocol of urinary and recombinant follicle-stimulating hormone used for ovarian stimulation of patients undergoing ICSI cycle

Differential effects of the charge variants of human follicle-stimulating hormone

NMR Studies of the Free α Subunit of Human Chorionic Gonadotropin

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