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J Biol Chem, Vol. 274, Issue 8, 5170-5184, February 19, 1999

Multiple Isoforms of Heparan Sulfate D-Glucosaminyl 3-O-Sulfotransferase
ISOLATION, CHARACTERIZATION, AND EXPRESSION OF HUMAN cDNAs AND IDENTIFICATION OF DISTINCT GENOMIC LOCI

Nicholas W. Shworak^§, Jian Liu, Lorin M. Petros, Lijuan Zhang, Masashi Kobayashi, Neal G. Copeland, Nancy A. Jenkins, and Robert D. Rosenberg^§

From the  Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, the ^§ Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, and the  Mammalian Genetics Laboratory, ABL-Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

3-O-Sulfated glucosaminyl residues are rare constituents of heparan sulfate and are essential for the activity of anticoagulant heparan sulfate. Cellular production of the critical active structure is controlled by the rate-limiting enzyme, heparan sulfate D-glucosaminyl 3-O-sulfotransferase-1 (3-OST-1) (EC 2.8.2.23). We have probed the expressed sequence tag data base with the carboxyl-terminal sulfotransferase domain of 3-OST-1 to reveal three novel, incomplete human cDNAs. These were utilized in library screens to isolate full-length cDNAs. Clones corresponding to predominant transcripts were obtained for the 367-, 406-, and 390-amino acid enzymes 3-OST-2, 3-OST-3_A, and 3-OST-3_B, respectively. These type II integral membrane proteins are comprised of a divergent amino-terminal region and a very homologous carboxyl-terminal sulfotransferase domain of ~260 residues. Also recovered were partial length clones for 3-OST-4. Expression of the full-length enzymes confirms the 3-O-sulfation of specific glucosaminyl residues within heparan sulfate (Liu, J., Shworak, N. W., Sina, P., Schwartz, J. J. Zhang, L., Fritze, L. M. S., and Rosenberg, R. D. (1999) J. Biol. Chem. 274, 5185-5192). Southern analyses suggest the human 3OST1, 3OST2, and 3OST4 genes, and the corresponding mouse isologs, are single copy. However, 3OST3A and 3OST3B genes are each duplicated in humans and show at least one copy each in mice. Intriguingly, the entire sulfotransferase domain sequence of the 3-OST-3_B cDNA (774 base pairs) was 99.2% identical to the same region of 3-OST-3_A. Together, these data argue that the structure of this functionally important region is actively maintained by gene conversion between 3OST3A and 3OST3B loci. Interspecific mouse back-cross analysis identified the loci for mouse 3Ost genes and syntenic assignments of corresponding human isologs were confirmed by the identification of mapped sequence-tagged site markers. Northern blot analyses indicate brain exclusive and brain predominant expression of 3-OST-4 and 3-OST-2 transcripts, respectively; whereas, 3-OST-3_A and 3-OST-3_B isoforms show widespread expression of multiple transcripts. The reiteration and conservation of the 3-OST sulfotransferase domain suggest that this structure is a self-contained functional unit. Moreover, the extensive number of 3OST genes with diverse expression patterns of multiple transcripts suggests that the novel 3-OST enzymes, like 3-OST-1, regulate important biologic properties of heparan sulfate proteoglycans.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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