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J. Biol. Chem., Vol. 281, Issue 9, 5348-5356, March 3, 2006

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Overexpression of Heparan Sulfate 6-O-Sulfotransferases in Human Embryonic Kidney 293 Cells Results in Increased N-Acetylglucosaminyl 6-O-Sulfation^*

Anh-Tri Do¹, Emanuel Smeds¹, Dorothe Spillmann, and Marion Kusche-Gullberg²

From the Department of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, P. O. Box 582, SE-751 23 Uppsala, Sweden and the Department of Biomedicine, Division of Physiology, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway

Heparan sulfate (HS) interacts with a variety of proteins and thus mediates numerous complex biological processes. These interactions critically depend on the patterns of O-sulfate groups within the HS chains that determine binding sites for proteins. In particular the distribution of 6-O-sulfated glucosamine residues influences binding and activity of HS-dependent signaling molecules. The protein binding domains of HS show large structural variability, potentially because of differential expression patterns of HS biosynthetic enzymes along with differences in substrate specificity. To investigate whether different isoforms of HS glucosaminyl 6-O-sulfotransferase (6-OST) give rise to differently sulfated domains, we have introduced mouse 6-OST1, 6-OST2, and 6-OST3 in human embryonic kidney 293 cells and compared the effects of overexpression on HS structure. High expression of any one of the 6-OST enzymes resulted in appreciably increased 6-O-sulfation of N-sulfated as well as N-acetylated glucosamine units. The increased 6-O-sulfation was accompanied by a decrease in nonsulfated as well as in iduronic acid 2-O-sulfated disaccharide structures. Furthermore, overexpression led to an altered HS domain structure, the most striking effect was the formation of extended 6-O-sulfated predominantly N-acetylated HS domains. Although the effect was most noticeable in 6-OST3-expressing cells, these results were largely independent of the particular 6-OST isoform expressed and mainly influenced by the level of overexpression.

Received for publication, August 31, 2005 , and in revised form, November 18, 2005.

^* This work was supported by Grant 13401 from the Swedish Research Council, the Swedish Foundation for Strategic Research (the Glycoconjugates in Biological Systems program), Polysackaridforskning AB (Uppsala, Sweden), and Konung Gustav V 80-års fond. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 47-55-58-66-90; Fax: 47-55-58-64-10; E-mail: Marion.Kusche{at}biomed.uib.no.

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