New Frontier in Glycoprotein Hormones and Their Receptors Structure–Function

Szkudlinski, Mariusz W.

doi:10.3389/fendo.2015.00155

Cited by 16 publications

(12 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pituitary gonadotropin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are synthesized in gonadotrope cells and play a key role in the control of gonadal function and reproduction (Huhtaniemi et al, 1982;Bousfield et al, 1996;Richards et al, 2002). Both gonadotropins, as well as placental chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH) produced by pituitary thyrotropes, belong to the family of glycoprotein hormones (GPH) (Pierce and Parsons, 1981; Ulloa-Aguirre and Szkudlinski, 2015).…”

Section: Introductionmentioning

confidence: 99%

The Follitropin Receptor: Matching Structure and Function

Ulloa‐Aguirre¹,

Zariñán²

2016

Mol Pharmacol

View full text Add to dashboard Cite

Follitropin, or follicle-stimulating hormone (FSH) receptor (FSHR), is a G protein-coupled receptor belonging to the glycoprotein hormone receptor family that plays an essential role in reproduction. Although its primary location is the gonad, the FSHR has also been reported in extragonadal tissues including bone, placenta, endometrium, liver, and blood vessels from a number of malignant tumors. The recently resolved crystal structure of FSH bound to the entire FSHR ectodomain has been instrumental in more clearly defining the role of this domain in ligand binding and receptor activation. Biochemical, biophysical, and structural data also indicate that the FSHR exists as a higher order structure and that it may heterodimerize with its closely related receptor, the luteinizing hormone receptor; this association may have physiologic implications during ovarian follicle maturation given that both receptors may simultaneously coexist in the same cell. FSHR heterodimerization is unique to the ovary because in the testes, gonadotropin receptors are expressed in separate compartments. FSHR self-association appears to be required for receptor coupling to multiple effectors and adaptors, for the activation of multiple signaling pathways and the transduction of asymmetric signaling, and for negative and positive receptor cooperativity. It also provides a mechanism through which the glycosylation variants of FSH may exert distinct and differential effects at the target cell level. Given its importance in regulating activation of distinct signaling pathways, functional selectivity at the FSHR is briefly discussed, as well as the potential implications of this particular functional feature on the design of new pharmacological therapies in reproduction.

show abstract

Section: Introductionmentioning

confidence: 99%

The Follitropin Receptor: Matching Structure and Function

Ulloa‐Aguirre¹,

Zariñán²

2016

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…1A). Mutation of all four residues to lysines results in the increase of binding affinity of hTSH to the hTSHR (Szkudlinski et al 1996, Szkudlinski 2015. Jiang et al (2012) proposed, based on the crystal structure of the FSH-FSHR ECD complex, that the TSHα mutations Q13K, E14K, P16K and Q20K are concentrated at the top side of the sulphated-Tyr binding pocket of the hormone, generating additional positive charges for a stronger interaction with the sulphated-Tyr of the receptor.…”

Section: Discussionmentioning

confidence: 99%

Glycosylation pattern analysis of glycoprotein hormones and their receptors

Miguel

Sanders

Furmaniak

et al. 2017

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

We have studied glycosylation patterns in glycoprotein hormones (GPHs) and glycoprotein hormone receptor (GPHR) extracellular domains (ECD) from different species to identify areas not glycosylated that could be involved in intermolecular or intramolecular interactions. Comparative models of the structure of the TSHR ECD in complex with TSH and in complex with TSHR autoantibodies (M22, stimulating and K1-70, blocking) were obtained based on the crystal structures of the FSH-FSHR ECD, M22-TSHR leucine-rich repeat domain (LRD) and K1-70-TSHR LRD complexes. The glycosylation sites of the GPHRs and GPHs from all species studied were mapped on the model of the human TSH TSHR ECD complex. The areas on the surfaces of GPHs that are known to interact with their receptors are not glycosylated and two areas free from glycosylation, not involved in currently known interactions, have been identified. The concave faces of GPHRs leucine-rich repeats 3-7 are free from glycosylation, consistent with known interactions with the hormones. In addition, four other non-glycosylated areas have been identified, two located on the receptors' convex surfaces, one in the long loop of the hinge regions and one at the C-terminus of the extracellular domains. Experimental evidence suggests that the non-glycosylated areas identified on the hormones and receptors are likely to be involved in forming intramolecular or intermolecular interactions.

show abstract

“…The essential biological properties of a compound that define its interaction with a putative target are: selectivity, potency, phenotypic efficacy (agonist, antagonist, allosteric modulator), target engagement, and bioavailability (Nunez, Venhorst, & Kruse, ; Kenakin, ; Szkudlinski, ). The first three properties reflect the pharmacodynamic (PD) properties of a compound, its effect on the target, cellular transduction cascade, tissue/system function, and whole animal phenotypic read out, while the latter two properties reflect its pharmacokinetic (PK) properties.…”

Section: Compound Validationmentioning

confidence: 99%

Section: Compound Biologymentioning

confidence: 99%

Reagent Validation to Facilitate Experimental Reproducibility

Williams

2018

CP Pharmacology

View full text Add to dashboard Cite

Many results reported in the biomedical research literature cannot be independently reproduced, undermining the basic foundations of science. This overview is intended for researchers who are committed to improving the quality and integrity of biomedical science by raising awareness of both the sources of irreproducibility, and activities specifically targeted to address the issue. The irreproducibility of biomedical research is due to a variety of factors, known and unknown, that markedly influence experimental outcomes. Among the known factors are inadequate training or mentoring, or experimenter incompetence. These may result in flawed experimental design and execution that reflect a lack of planning, leading to an underpowering of a study, an absence of appropriate controls, selective data analysis, inappropriate statistical analysis, and/or investigator bias or fraud. Another frequently overlooked source of irreproducibility is failure to ensure that the equipment used is performing up to manufacturer specifications. Failure to validate/authenticate the experimental reagents is another source of irreproducibility. These include compounds, cell lines, antibodies, and the animal models used in a study. This overview discusses how a lack of validation of research reagents negatively impact experimental reproducibility, and provides guidelines to avoid these pitfalls. © 2018 by John Wiley & Sons, Inc.

show abstract

New Frontier in Glycoprotein Hormones and Their Receptors Structure–Function

Cited by 16 publications

References 85 publications

The Follitropin Receptor: Matching Structure and Function

The Follitropin Receptor: Matching Structure and Function

Glycosylation pattern analysis of glycoprotein hormones and their receptors

Reagent Validation to Facilitate Experimental Reproducibility

Contact Info

Product

Resources

About