Structural features of mammalian gonadotropins.
Abstract: There are two species for which both pituitary and placental gonadotropins are readily available, humans and horses. The human gonadotropins are better characterized than equine gonadotropins. Nevertheless, the latter are very interesting because they provide exceptions to some of the general structure-function principles derived from studies on human and other mammalian gonadotropins. For example, separate genes encode the hLH beta and hCG beta subunits while a single gene encodes eLH beta and eCG beta. Thus, eCG and eLH differ only in their oligosaccharide moieties and eLH is the only LH that possesses the O-glycosylated C-terminal extension previously believed to be restricted to chorionic gonadotropins. Truncation experiments involving eLH beta and hCG beta have suggested the C-terminal extension has no effect on receptor binding. However, the largest of three eCG forms which differ only in the extent of O-glycosylation possessed reduced affinity for LH and FSH receptors. This result suggested that effects of O-glycosylation need to be considered when examining the glycosylation differences between eLH and eCG responsible for the 10-fold lower eCG receptor binding affinity compared with that of eLH. Contribution of alpha Asn56 N-linked oligosaccharides to the different biological activities of eLH and eCG has been evaluated following selective removal using peptide-N-glycanase digestion of native equine alpha-subunit preparations. Hormones-specific patterns of glycosylation were observed on alpha Asn56 of eLH, eFSH, and eCG. Removal of alpha Asn56 oligosaccharides increased the rate of subunit association, the extent of association, and receptor binding activity. Some unassociated alpha-subunit oligosaccharides were identified which may interfere with subunit association because they were more abundant in unassociated subunit oligosaccharide maps than in a total oligosaccharide map. This was most striking in the case of eCG alpha in which two minor peaks became the major oligosaccharide peaks detectable in the unassociated eCG alpha fraction following association with eLH beta and eFSH beta. The biological activities exhibited by hybrid hormones, eLH alpha reassociated with oLH beta and pLH beta, found to be greater than those of oLH and pLH provided an interesting exception to the general rule that the beta-subunit determines the potency of the heterodimer. LH receptor binding activities of eLH beta-chimeric ovine/equine alpha-subunits suggested that the equine alpha-subunit N-terminal domain may be responsible for this effect. Equine FSH has higher FSH receptor binding activity than human, ovine, and porcine FSH preparations. This probably results from two factors. First, the presence of the equine alpha-subunit promotes receptor binding as noted above. Second, the overall -2 charge of the eFSH beta determinant loop, which is less negative that the -3 observed in other species, results from the presence of an Asn residue at position 88 instead of Asp. This apparently facilitates binding to the FSH receptor.
Publication Date: 1996-12-20 PubMed ID: 9027339DOI: 10.1016/s0303-7207(96)03945-7Google Scholar: Lookup
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- Comparative Study
- Journal Article
- Research Support
- U.S. Gov't
- P.H.S.
- Review
Summary
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The study investigates the unique structural compositions of gonadotropins — hormones that stimulate the gonads — in humans and horses. A significant finding indicates that horses’ gonadotropins provide exceptions to the general principles derived from studies on humans, suggesting functions of glycosylation and subunit associations in the biological activities of these hormones.
Analysis of Human and Equine Gonadotropins
- The study looks into available human and horse gonadotropins, noting that equine gonadotropins provide interesting deviations to the established structure-function principles learned from studying human and other mammalian gonadotropins.
- Detailed examination reveals that separate genes encode human LH (luteinizing hormone) beta and human CG (chorionic gonadotropin) beta subunits, whereas a single gene encodes for both equine LH beta and equine CG beta.
Glycosylation and Its Impact on Hormone Activity
- The role of glycosylation — the process where sugars attach to proteins or lipids — is crucial in the unearthing of hormone activity differences between eLH and eCG, particularly in understanding the tenfold lower eCG receptor binding affinity compared to eLH.
- There is an instance where more extensive O-glycosylation of eCG resulted in reduced affinity for LH and FSH receptors. This highlights that O-glycosylation plays a pivotal role and needs to be considered in studies on glycosyl differences.
Subunit Association and its Effects on Receptor Binding
- Another important result shows that when alpha Asn56 oligosaccharides (a specific type of sugar) are removed, the rate of subunit association, the extent of this association, and receptor binding activity all increase.
- There are unassociated alpha-subunit oligosaccharides that could potentially interfere with subunit association.
Enhanced Biological Activities of Hybrid Hormones
- Hybrid hormones like eLH alpha reassociated with oLH beta and pLH beta exhibited increased biological activities, which defies the common theory suggesting that the beta-subunit determines the heterodimer’s potency.
FSH Receptor Binding Activity
- The study also reveals that equine FSH (follicle-stimulating hormone) has higher FSH receptor binding activity than its counterparts in human, ovine, and porcine species. This could be attributed to the presence of the equine alpha-subunit, promoting receptor binding, and the net negative charge of the eFSH beta determinant loop.
Cite This Article
APA
Bousfield GR, Butnev VY, Gotschall RR, Baker VL, Moore WT.
(1996).
Structural features of mammalian gonadotropins.
Mol Cell Endocrinol, 125(1-2), 3-19.
https://doi.org/10.1016/s0303-7207(96)03945-7 Publication
Researcher Affiliations
- Department of Biological Sciences, Wichita State University, KS 67260-0026, USA.
MeSH Terms
- Amino Acid Sequence
- Animals
- Chorionic Gonadotropin / chemistry
- Chorionic Gonadotropin / metabolism
- Follicle Stimulating Hormone / chemistry
- Follicle Stimulating Hormone / metabolism
- Glycosylation
- Gonadotropins / chemistry
- Horses
- Humans
- Luteinizing Hormone / chemistry
- Luteinizing Hormone / metabolism
- Molecular Sequence Data
- Recombinant Fusion Proteins
Grant Funding
- HD-29047 / NICHD NIH HHS
Citations
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