Structural Analysis of the Oligosaccharides Derived from Glycodelin, a Human Glycoprotein with Potent Immunosuppressive and Contraceptive Activities

Dell, Anne; Morris, Howard R.; Easton, Richard L.; Panico, Maria; Patankar, Manish S.; Oehninger, Sergio; Koistinen, Hannu; Koistinen, Hannu; Seppälä, Markku; Clark, Gary F.

doi:10.1074/jbc.270.41.24116

Cited by 233 publications

(232 citation statements)

References 62 publications

(57 reference statements)

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“…Like gal1, PP14 also induces T cell apoptosis (32), colocalizes with CD45 on the cells to which it binds (33), and reacts with N-acetyllactosamines (34). Interestingly, PP14 is also expressed by glandular epithelium around which apoptotic T cells are seen, and has poly-N-acetyllactosamine moieties (35) to which gal1 could potentially bind. An interesting difference between the 2 proteins is that whereas ␣-2,6-sialylation of CD45 glycans on T cells negatively regulates gal1-induced apoptosis, it favors the activity of PP14 (22,34).…”

Section: Discussionmentioning

confidence: 99%

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

Kopcow

Rosetti²,

Leung³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

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The human fetus is not rejected by the maternal immune system despite expressing paternal antigens. Natural killer cells, the major lymphocyte population of the human decidua (dNKs), express genes with immunomodulatory potential. These include galectin-1 (gal1), a lectin with apoptotic activity on activated CD8 ؉ T cells, Th1 and Th17 CD4 ؉ cells. Although many cell types at the maternalfetal interface also produce gal1, its production by dNKs has been used here to study its function in pregnancy. Media conditioned by dNKs containing gal1 induced apoptosis of activated T cells. This effect was blocked by anti-gal1 antibodies. Decidual T (dT) cells but not peripheral T (pT) cells bound gal1 and presented a distinct glycophenotype compatible with sensitivity to gal1. Annexin V staining, TUNEL, and hypodiploidy showed a substantial proportion of apoptotic dT cells. Immunohistochemistry revealed widespread expression of gal1 as well as periglandular apoptotic dT foci that colocalized with dNKs. Thus, secretion of gal1 by dNKs and other decidual cells contributes to the generation of an immuneprivileged environment at the maternal-fetal interface.maternal-fetal tolerance ͉ NK cells ͉ lectin ͉ decidua

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Section: Discussionmentioning

confidence: 99%

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

Kopcow

Rosetti²,

Leung³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

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“…In the human body, typical LacdiNAc structures have been found in N-glycans of LH (29,30), TSH (25), glycodelin-A (26,27), TFPI (28), and tenascin-R (49). LH and TSH are produced in the pituitary gland.…”

Section: Discussionmentioning

confidence: 99%

“…LacdiNAc, a special structure in human N-glycans, has been found in certain glycoproteins and glycohormones, such as lutropin (LH) (24), thyrotropin (TSH) (25), glycodelin-A (26,27), tissue factor pathway inhibitor (TFPI) produced in human embryonic kidney (HEK) 293 cells (28), and so on. LH is a pituitary glycoprotein hormone that is essential for the regulation of follicular maturation, ovulation, and the secretion of estradiol and progesterone.…”

mentioning

confidence: 99%

Molecular Cloning and Characterization of a Novel Human β1,4-N-Acetylgalactosaminyltransferase, β4GalNAc-T3, Responsible for the Synthesis of N,N′-Diacetyllactosediamine, GalNAcβ1–4GlcNAc

Sato

Gotoh

Kiyohara

et al. 2003

Journal of Biological Chemistry

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We found a novel human glycosyltransferase gene carrying a hypothetical ␤1,4-glycosyltransferase motif during a BLAST search, and we cloned its full-length open reading frame by using the 5 -rapid amplification of cDNA ends method. It encodes a type II transmembrane protein of 999 amino acids with homology to chondroitin sulfate synthase in its C-terminal region (GenBank TM accession number AB089940). Its putative orthologous gene was also found in mouse (accession number AB114826). The truncated form of the human enzyme was expressed in HEK293T cells as a soluble protein. The recombinant enzyme transferred GalNAc to GlcNAc ␤-benzyl. The product was deduced to be GalNAc␤1-4GlcNAc␤-benzyl based on mass spectrometry and NMR spectroscopy. We renamed the enzyme ␤1,4-N-acetylgalactosaminyltransferase-III (␤4GalNAc-T3). ␤4GalNAc-T3 effectively synthesized N,N -diacetylgalactosediamine, GalNAc␤1-4GlcNAc, at non-reducing termini of various acceptors derived not only from N-glycans but also from O-glycans. Quantitative real time PCR analysis showed that its transcript was highly expressed in stomach, colon, and testis. As some glycohormones contain N,N -diacetylgalactosediamine structures in their N-glycans, we examined the ability of ␤4GalNAc-T3 to synthesize N,N -diacetylgalactosediamine structures in N-glycans on a model protein.When fetal calf fetuin treated with neuraminidase and ␤1,4-galactosidase was utilized as an acceptor protein, ␤4GalNAc-T3 transferred GalNAc to it. Furthermore, the majority of the signal from GalNAc disappeared on treatment with glycopeptidase F. These results suggest that ␤4GalNAc-T3 could transfer GalNAc residues, producing N,N -diacetylgalactosediamine structures at least in Nglycans and probably in both N-and O-glycans.

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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.…”

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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...

show abstract

Structural Analysis of the Oligosaccharides Derived from Glycodelin, a Human Glycoprotein with Potent Immunosuppressive and Contraceptive Activities

Cited by 233 publications

References 62 publications

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

Molecular Cloning and Characterization of a Novel Human β1,4-N-Acetylgalactosaminyltransferase, β4GalNAc-T3, Responsible for the Synthesis of N,N′-Diacetyllactosediamine, GalNAcβ1–4GlcNAc

Closely Related Mammals Have Distinct Asialoglycoprotein Receptor Carbohydrate Specificities

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