Glycosylation pattern analysis of glycoprotein hormones and their receptors

Miguel, Ricardo Núñez; Sanders, Jane; Furmaniak, Jadwiga; Smith, Bernard Rees

doi:10.1530/jme-16-0169

Cited by 12 publications

(4 citation statements)

References 79 publications

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“…The rationale supporting the glycoform-specific activity relies on the assumption that different oligosaccharide chains may modulate the hormone-receptor structural interaction [58,60,61] and the downstream signaling cascades [57,58,62]. These considerations generated the idea that FSH variants could act as biased receptor agonists [63] and the impact of carbohydrate heterogeneity on FSH bioactivity was investigated both in vitro and in vivo [57,58].…”

Section: Fsh In Therapymentioning

confidence: 99%

FSH for the Treatment of Male Infertility

Casarini

Crépieux

Reiter

et al. 2020

IJMS

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Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.

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Section: Fsh In Therapymentioning

confidence: 99%

FSH for the Treatment of Male Infertility

Casarini

Crépieux

Reiter

et al. 2020

IJMS

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“…5). The residues, His70, His95 and Asp120, are located in an area that has been previously predicted as a possible oligomerisation site (Núñez Miguel et al 2017). However, the relative orientations of the molecules in each dimer are different.…”

Section: M22mentioning

confidence: 84%

“…In the extracellular domain of the TSHR there are six asparagines that conform to the consensus sequence for N-linked glycosylation (Asn-Xxx-Ser/Thr, where Xxx is any amino acid except proline), Asn77, Asn99, Asn113, Asn177, Asn198, Asn302 (Núñez Miguel et al 2017), and previous studies have indicated that all six glycosylation sites are glycosylated (Tanaka et al 1998). All five of the glycosylation sites that are within the TSHR260 domain have observed glycans attached in the TSHR-M22 structure ) and four of the sites (Asn77, Asn99, Asn177 and Asn198) have glycans observed in the TSHR-K1-70 structure (Sanders et al 2011).…”

Section: Crystal Structurementioning

confidence: 99%

Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain

Miller-Gallacher

Sanders

Young

et al. 2019

Journal of Molecular Endocrinology

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The crystal structures of the thyroid-stimulating hormone receptor (TSHR) leucine-rich repeat domain (amino acids 22-260; TSHR260) in complex with a stimulating human monoclonal autoantibody (M22 TM ) and in complex with a blocking human autoantibody (K1-70™) have been solved. However, attempts to purify and crystallise free TSHR260, that is not bound to an autoantibody, have been unsuccessful due to the poor stability of free TSHR260. We now describe a TSHR260 mutant that has been stabilised by the introduction of six mutations (H63C, R112P, D143P, D151E, V169R and I253R) to form TSHR260-JMG55 TM , which is approximately 900 times more thermostable than wild-type TSHR260. These six mutations did not affect the binding of human TSHR monoclonal autoantibodies or patient serum TSHR autoantibodies to the TSHR260. Furthermore, the response of full-length TSHR to stimulation by TSH or human TSHR monoclonal autoantibodies was not affected by the six mutations. Thermostable TSHR260-JMG55 TM has been purified and crystallised without ligand and the structure solved at 2.83 Å resolution. This is the first reported structure of a glycoprotein hormone receptor crystallised without ligand. The unbound TSHR260-JMG55 TM structure and the M22 and K1-70 bound TSHR260 structures are remarkably similar except for small changes in side chain conformations. This suggests that neither the mutations nor the binding of M22 TM or K1-70 TM change the rigid leucine-rich repeat domain structure of TSHR260. The solved TSHR260-JMG55 TM structure provides a rationale as to why the six mutations have a thermostabilising effect and provides helpful guidelines for thermostabilisation strategies of other soluble protein domains.

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“…Interestingly, the abundance of the glycosylated variants in FSHβ subunit appears to be physiologically regulated (141). Although glycosylations are involved in the FSH bioactivity, they are not directly interacting with the receptor binding site (11, 12, 15, 150). Removal of the carbohydrate residue at position 78 from α-subunit significantly increases receptor binding affinity of human FSH.…”

Section: Biased Signaling At the Fshrmentioning

confidence: 99%

Biased Signaling and Allosteric Modulation at the FSHR

et al. 2019

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Knowledge on G protein-coupled receptor (GPCRs) structure and mechanism of activation has profoundly evolved over the past years. The way drugs targeting this family of receptors are discovered and used has also changed. Ligands appear to bind a growing number of GPCRs in a competitive or allosteric manner to elicit balanced signaling or biased signaling (i.e., differential efficacy in activating or inhibiting selective signaling pathway(s) compared to the reference ligand). These novel concepts and developments transform our understanding of the follicle-stimulating hormone (FSH) receptor (FSHR) biology and the way it could be pharmacologically modulated in the future. The FSHR is expressed in somatic cells of the gonads and plays a major role in reproduction. When compared to classical GPCRs, the FSHR exhibits intrinsic peculiarities, such as a very large NH2-terminal extracellular domain that binds a naturally heterogeneous, large heterodimeric glycoprotein, namely FSH. Once activated, the FSHR couples to Gαs and, in some instances, to other Gα subunits. G protein-coupled receptor kinases and β-arrestins are also recruited to this receptor and account for its desensitization, trafficking, and intracellular signaling. Different classes of pharmacological tools capable of biasing FSHR signaling have been reported and open promising prospects both in basic research and for therapeutic applications. Here we provide an updated review of the most salient peculiarities of FSHR signaling and its selective modulation.

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Glycosylation pattern analysis of glycoprotein hormones and their receptors

Cited by 12 publications

References 79 publications

FSH for the Treatment of Male Infertility

FSH for the Treatment of Male Infertility

Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain

Biased Signaling and Allosteric Modulation at the FSHR

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