From legumes to leukocytes: biological roles for sulfated carbohydrates

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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).

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Xia¹,

Evers²,

Kang³

et al. 2000

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“…Unique carbohydrate structures found on a number of glycoproteins are believed to contribute to biological functions ranging from transport of lysosomal enzymes to lysosomes (1,2), to regulation of circulatory half-life of hormones (3,4), to cellular recognition (5,6). The addition of unique carbohydrate structures to select glycoproteins requires a "recognition determinant," a feature encoded in the peptide portion of these glycoproteins, to be recognized by one or more of the transferases responsible for their synthesis.…”

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confidence: 99%

A Necessary and Sufficient Determinant for Protein-selective Glycosylation in Vivo

Miller

Fiete

Blake³

et al. 2008

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A limited number of glycoproteins including luteinizing hormone and carbonic anhydrase-VI (CA6) bear N-linked oligosaccharides that are modified with ␤1,4-linked N-acetylgalactosamine (GalNAc). The selective addition of GalNAc to these glycoproteins requires that the ␤1,4-N-acetylgalactosaminyltransferase (␤GT) recognize both the oligosaccharide acceptor and a peptide recognition determinant on the substrate glycoprotein. We report here that two recently cloned ␤GTs, ␤GT3 and ␤GT4, that are able to transfer GalNAc to GlcNAc in ␤1,4-linkage display the necessary glycoprotein specificity in vivo. Both ␤GTs transfer GalNAc to N-linked oligosaccharides on the luteinizing hormone ␣ subunit and CA6 but not to those on transferrin (Trf). A single peptide recognition determinant encoded in the carboxyl-terminal 19-amino acid sequence of bovine CA6 mediates transfer of GalNAc to each of its two N-linked oligosaccharides. The addition of this 19-amino acid sequence to the carboxyl terminus of Trf confers full acceptor activity onto Trf for both ␤GT3 and ␤GT4 in vivo. The complete 19-amino acid sequence is required for optimal GalNAc addition in vivo, indicating that the peptide sequence is both necessary and sufficient for recognition by ␤GT3 and ␤GT4.

“…Critical roles of carbohydrate sulfation have been demonstrated in binding to growth factors, chemokines, hormones, anti-coagulation factors, and cell adhesion molecules (1)(2)(3)(4)(5). In addition to sulfatide, carbohydrates with 3Ј-sulfated ␤-Gal linkages are present in both O-glycans (6) and N-linked glycans (7).…”

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confidence: 99%

A Novel Human Gal-3-O-Sulfotransferase

El-Fasakhany¹,

Uchimura²,

Kannagi³

et al. 2001

Based on sequence homology with the previously cloned human cerebroside sulfotransferase (CST) cDNA, a novel sulfotransferase was cloned by screening a human fetal brain cDNA library. The novel sulfotransferase gene was present on human chromosome 11q13; the location was different from human CST and from that of the recently cloned human ␤-Gal 3-sulfotransferase (GP3ST). The isolated cDNA contained an open reading frame that encoded a predicted protein of 431 amino acid residues with type II transmembrane topology. The amino acid sequence showed 33% identity with that of human CST and 38% with that of human GP3ST. The recombinant enzyme expressed in Chinese hamster ovary cells catalyzed transfer of sulfate to position 3 of non-reducing ␤-galactosyl residues in Gal␤1-4GlcNAc. Type 2 chains served as good acceptors, whereas type 1 chains served as poor acceptors, and intermediate activity was found toward Gal␤1-3GalNAc. Therefore, the substrate specificity was different from that of GP3ST. CST activity was not detected in the newly cloned enzyme. Northern blotting analysis showed that the sulfotransferase mRNA was strongly expressed in the thyroid and moderately expressed in the brain, heart, kidney, and spinal cord. Co-transfection of the enzyme cDNA and fucosyltransferase III into COS-7 cells resulted in expression of (SO 4 -3)Gal␤1-4(Fuc␣1-3)GlcNAc and a small amount of (SO 4 -3)Gal␤1-3(Fuc␣1-4)GlcNAc. These results indicated that the newly cloned enzyme is a novel Gal-3-O-sulfotransferase and is involved in biosynthesis of the (SO 4 -3)Gal␤1-4(Fuc␣1-3)GlcNAc structure.Sulfation of carbohydrates attached to glycoproteins, glycolipids, and proteoglycans confers highly specific functions on these macromolecules. Critical roles of carbohydrate sulfation have been demonstrated in binding to growth factors, chemokines, hormones, anti-coagulation factors, and cell adhesion molecules (1-5). In addition to sulfatide, carbohydrates with 3Ј-sulfated ␤-Gal linkages are present in both O-glycans (6) and N-linked glycans (7). Recently, (SO 4 -3)Gal␤1-4(Fuc␣1-3)GlcNAc (3Ј-sulfo Le X