Molecular structures of glycoprotein hormones and functions of their carbohydrate components

Hartree, Anne Stockell; Renwick, A. G.

doi:10.1042/bj2870665

Cited by 146 publications

(80 citation statements)

References 242 publications

(245 reference statements)

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“…The levels of hormone-specific GalNAc-transferase changes in parallel to those of LH (56). Since the terminal GalNAc on the N-linked oligosaccharides of LH and other glycoproteins can also be modified with terminal ␣2,6-linked sialic acid (3,13,26,(57)(58)(59)(60)(61)(62), the levels of GalNAc-4-sulfotransferase as well as ␣2,6-sialyltransferase may determine which structure is ultimately present on LH and other glycoproteins bearing such oligosaccharides. This would have a profound impact on both the rate and the site of clearance for LH.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Expression of the Pituitary Glycoprotein HormoneN-Acetylgalactosamine-4-O-sulfotransferase

Xia¹,

Evers²,

Kang³

et al. 2000

Journal of Biological Chemistry

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The pituitary hormones LH, 1 thyrotropin, and pro-opiomelanocortin bear unique N-linked oligosaccharides that terminate with the sequence SO 4 -4-GalNAc␤1,4GlcNAc␤1,2Man␣ (1-6).The terminal GalNAc-4-SO 4 is recognized by a receptor, the Man/GalNAc-4-SO 4 receptor (7-9), which is located in hepatic endothelial cells and controls the circulatory half-life of LH and other glycoproteins bearing this structure (10, 11). A short circulatory half-life in conjunction with the regulated release from storage granules in the gonadotroph produces the episodic rise and fall seen in circulating LH levels (12, 13). This is essential for efficient activation of the LH receptor in the ovary and testis due to the down-regulation and internalization of the activated receptor by ␤-arrestin (14). Sequential actions of a hormone-specific ␤1,4 GalNAc-transferase and a GalNAc-4-sulfotransferase are required for the synthesis of GalNAc-4-SO 4 on LH and other glycoproteins (13,(15)(16)(17)(18)(19). Three key functions have been conserved throughout vertebrate evolution: 1) the peptide recognition determinant utilized by the GalNAc-transferase, 2) the GalNAc-transferase itself, and 3) the GalNAc-4-sulfotransferase. As a result, Nlinked structures terminating with ␤1,4-linked GalNAc-4-SO 4 occur on glycoprotein hormones from all vertebrate species (20). GalNAc-transferase and GalNAc-4-sulfotransferase activities with the same properties as those expressed in the pituitary have been detected in other tissues and cells (21). Furthermore, a number of other glycoproteins bearing N-and O-linked structures terminating with ␤1,4-linked GalNAc-4-SO 4 have been described (2,5,(22)(23)(24)(25)(26). Thus, oligosaccharides terminating with GalNAc-4-SO 4 may fulfill a number of different roles in vivo.Recently the HNK-1 sulfotransferase (HNK-1 ST), a glucuronyl-3-sulfotransferase that mediates synthesis of the HNK-1 epitope SO 4 -3-GlcA␤1,3Gal␤1,4GlcNAc (27) was cloned (28, 29). The HNK-1 structure is found in the central and peripheral nervous systems on glycolipids and glycoproteins involved in neural recognition and synaptogenesis (Ref. 30; for reviews, see Refs. 31 and 32). Expression of the HNK-1 structure is spatially and temporally regulated, suggesting an important role in axon outgrowth (33). It is a predominant autoantigen in demyelinating diseases of the peripheral nervous system (34). Recently this glycan has been recognized to be a crucial player in synaptic plasticity involving inhibitory interneurons in the hippocampus (35). The sulfate group of the HNK-1 glycan is essential for its function (36, 37).

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Section: Discussionmentioning

confidence: 99%

Molecular Cloning and Expression of the Pituitary Glycoprotein HormoneN-Acetylgalactosamine-4-O-sulfotransferase

Xia¹,

Evers²,

Kang³

et al. 2000

Journal of Biological Chemistry

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“…Because the prolactin-like hormones bearing N-linked oligosaccharides terminating with the sequence Sia␣2,6GalNAc␤1,4GlcNAc are synthesized during the last third of pregnancy in the placenta of the rat (12), they may represent the first examples of endogenous ligands for the ASGP-R. Although rare, the terminal sequence Sia␣2,6GalNAc␤1,4GlcNAc has been found on a number of glycoproteins in addition to the prolactin-like hormones (12) including glycodelin from human amniotic fluid (13), pituitary glycoprotein hormones (14,15), and recombinant human protein C (16). The presence of these structures on multiple glycoproteins raises the possibility that the ASGP-R in other mammalian species may also recognize oligosaccharides terminating with the sequence Sia␣2,6GalNAc␤1,4GlcNAc.…”

mentioning

confidence: 99%

Closely Related Mammals Have Distinct Asialoglycoprotein Receptor Carbohydrate Specificities

Park

Baenziger

2004

Journal of Biological Chemistry

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We recently reported that the rat asialoglycoprotein receptor binds oligosaccharides terminating with sialic acid (Sia) ␣2,6GalNAc. Despite a high percentage of identical amino acids in their sequences, orthologues of the asialoglycoprotein receptor (ASGP-R) in different mammals differ in their specificity for terminal Sia␣2,6GalNAc. The recombinant subunit 1 of the ASGP-R from the rat (RHL-1 or rat hepatic lectin) and the mouse (MHL-1 or mouse hepatic lectin), which differ at only 12 positions in the amino acid sequence of their carbohydrate recognition domains, binds Sia␣2,6GalNAc␤1,4GlcNAc␤1,2Man-bovine serum albumin and GalNAc␤1,4GlcNAc␤1,2Man-bovine serum albumin in ratios of 16:1.0 and 1.0:1.0, respectively. Mutagenesis was used to show that amino acids both in the immediate vicinity of the proposed binding site for terminal GalNAc and on the ␣2 helix that is distant from the binding site contribute to the specificity for terminal Sia␣2,6GalNAc. Thus, multiple amino acid sequence alterations in two key locations contribute to the difference in specificity observed for the rat and mouse ASGP-Rs. We hypothesize that the altered specificity of ASPG-R orthologues in such evolutionarily closely related species reflects rapidly changing requirements for recognition of endogenous or exogenous oligosaccharides in vivo.The hepatic asialoglycoprotein receptor (ASGP-R) 1 identified by Van Den Hamer et al. (1) was the first mammalian lectin to be described. A characteristic of the receptor is its ability to rapidly remove glycoproteins from the circulation that have been treated with neuraminidase or mild acid (2). Rapid clearance reflects the specificity of the ASGP-R for terminal ␤-linked galactose (Gal) or N-acetylgalactosamine (GalNAc) residues that are exposed by the removal of terminal sialic acid (Sia). The ASGP-R was subsequently shown to be a hetero-oligomer consisting of two highly homologous subunits, hepatic lectin subunits 1 and 2 (HL-1 and HL-2, respectively) (3-5). Whereas both subunits are required for the endocytosis of ligands, the carbohydrate binding activity is associated predominantly with HL-1 (6, 7). Prior structural and functional studies of the ASGP-R have included the crystallization of human and the generation of mice with genetically ablated HL-2 (9) and HL-1 (10). These studies have been informative but have not revealed the identity of endogenous ligands that may be recognized by the ASGP-R in vivo.We recently reported that, in the rat, the ASGP-R mediates the rapid clearance of bovine serum albumin bearing multiple chemically coupled tetrasaccharides with the sequence Sia␣2,6GalNAc␤1,4GlcNAc␤1,2Man (Sia␣2,6GGnM-bovine serum albumin (BSA)) (11). Because the prolactin-like hormones bearing N-linked oligosaccharides terminating with the sequence Sia␣2,6GalNAc␤1,4GlcNAc are synthesized during the last third of pregnancy in the placenta of the rat (12), they may represent the first examples of endogenous ligands for the ASGP-R. Although rare, the terminal sequence Sia␣2,6GalNAc␤1,4GlcNAc h...

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“…Glycoprotein hormones consist of α and β subunits. Each subunit is a single polypeptide chain, which is covalently attached to one or more oligosaccharides (Stockell Hartree and Renwick 1992). Th us, glycoprotein hormones are non-covalent heterodimers comprising a common α-subunit and a hormone-specifi c β-subunit.…”

Section: Th E Unique Structure Of Thyrostimulinmentioning

confidence: 99%

The role of thyrostimulin and its potential clinical significance

Karponis

Ananth

2017

Endocrine Regulations

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Th yrostimulin is a glycoprotein heterodimer of GPA2 and GPB5, fi rst described in 2002. It is involved in the physiological function of several tissues. Moreover, evidence points towards the ability of thyrostimulin's individual monomers to induce a biological eff ect, which could denote the circulatory/systemic eff ects of the molecule when found in higher concentrations. From the evolutionary point of view, thyrostimulin shares a binding epitope with the thyroid-stimulating hormone for the thyroid stimulating hormone receptor, whilst possessing affi nity for another unique binding site on the same receptor. Although thyrostimulin can be involved in the hypothalamicpituitary-thyroid axis, its presence in various tissues in an eclectic array of diff erent species renders it multifunctional. From weight loss via increasing metabolic rate to progression of cancer in human ovaries, it is certainly not a signaling molecule to overlook. Furthermore, thyrostimulin has been implicated in bone metabolism, acute illness, and reproductive function. In summary, to our knowledge, this is the fi rst review dealing with the physiological role of thyrostimulin and its potential applications in the clinical practice.

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Molecular structures of glycoprotein hormones and functions of their carbohydrate components

Cited by 146 publications

References 242 publications

Molecular Cloning and Expression of the Pituitary Glycoprotein HormoneN-Acetylgalactosamine-4-O-sulfotransferase

Molecular Cloning and Expression of the Pituitary Glycoprotein HormoneN-Acetylgalactosamine-4-O-sulfotransferase

Closely Related Mammals Have Distinct Asialoglycoprotein Receptor Carbohydrate Specificities

The role of thyrostimulin and its potential clinical significance

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