Abstract
N-Linked oligosaccharides terminating with the sequence SO(4)-4-GalNAcbeta1,4GlcNAcbeta1,2Manalpha are present on the pituitary hormones lutropin (LH), thyrotropin, and pro-opiomelanocortin. The sulfated structures on LH are essential for expression of its biologic function in vivo. We have cloned the N-acetylgalactosamine-4-sulfotransferase (GalNAc-4-ST1, GenBank(TM) accession number ), which mediates sulfate addition to the N-linked oligosaccharides on LH and other pituitary glycoproteins with terminal (beta1,4-linked GalNAc based on its homology to HNK-1 sulfotransferase (HNK-1 ST). GalNAc-4-ST1 displays 23% identity to HNK-1 ST and 28% to chondroitin 4-sulfotransferase 1 (C4ST-1) and 26% to chondroitin 4-sulfotransferase 2 (C4ST-2). The cDNA predicts a type II transmembrane protein of 424 amino acids with four potential N-linked glycosylation sites and a single membrane-spanning domain. GalNAc-4-ST1 has putative 5'-phosphosulfonate and 3'-phosphate binding sites. Three more carboxyl-terminal regions of unknown function also show a high degree of identity with HNK-1 ST, C4ST-1, and C4ST-2. The membrane-bound form of GalNAc-4-ST1 transfers sulfate to GalNAcbeta1, 4GlcNAcbeta-R but not to chondroitin, whereas truncated forms of GalNAc-4-ST1 that are released into the medium transfer sulfate to both GalNAcbeta1,4GlcNAcbeta-R and chondroitin. The first 118 amino acids of GalNAc-4-ST1 appear to contribute to both its activity and specificity for terminal beta1,4-linked GalNAc. GalNAc-4-ST1 also efficiently transfers sulfate to N-linked oligosaccharides on native LH and other glycoproteins terminating with beta1,4-linked GalNAc. A single transcript of 2.4 kilobases is most highly expressed in the pituitary and other regions of the central nervous system. The GalNAc-4-ST1 gene is located on human chromosome 19q13.1.
Highlights
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF300612
Cloning the cDNA for the GalNAc-4-sulfotransferase responsible for sulfate addition to the N-linked oligosaccharides on LH represents an important advance in our understanding of the biologic significance of this highly conserved element of glycoprotein hormone biology
The glycoprotein hormones LH and thyrotropin were the first mammalian glycoproteins demonstrated to bear N-linked oligosaccharides terminating with the unique sequence SO4-4-GalNAc1,4GlcNAc1,2Man␣ [51, 52]. This sulfated structure was subsequently described on a limited number of other glycoproteins that are synthesized in the pituitary and in other tissues [2, 5, 22,23,24,25,26, 53,54,55]
Summary
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF300612. This GalNAc-4-sulfotransferase, highly expressed in the pituitary and other regions of the brain, is active with substrates terminating with GalNAc1,4GlcNAc-R, including the glycoprotein hormone LH. We examined GalNAc-4-ST1 for its ability to transfer sulfate to glycoproteins, such as the glycoprotein hormones LH and thyrotropin and carbonic anhydrase VI, which bear Nlinked oligosaccharides terminating with the sequence SO4-4GalNAc1,4 GlcNAc1,2Man␣.
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