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Originally published In Press as doi:10.1074/jbc.M002990200 on June 22, 2000

J. Biol. Chem., Vol. 275, Issue 36, 27733-27740, September 8, 2000
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Location of the Glucuronosyltransferase Domain in the Heparan Sulfate Copolymerase EXT1 by Analysis of Chinese Hamster Ovary Cell Mutants*

Ge WeiDagger §, Xiaomei BaiDagger , Mary M. G. GabbDagger , Karen J. Bame, Thomas I. Koshy||**, Patricia G. Spear||, and Jeffrey D. EskoDagger §§

From the Dagger  Department of Cellular and Molecular Medicine, Glycobiology Research and Training Program, University of California, San Diego, La Jolla, California, 92093-0687,  Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri 64110, and the || Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611

Heparan sulfate formation occurs by the copolymerization of glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc) residues. Recent studies have shown that these reactions are catalyzed by a copolymerase encoded by EXT1 and EXT2, members of the exostosin family of putative tumor suppressors linked to hereditary multiple exostoses. Previously, we identified a collection of Chinese hamster ovary cell mutants (pgsD) that failed to make heparan sulfate (Lidholt, K., Weinke, J. L., Kiser, C. S., Lugemwa, F. N., Bame, K. J., Cheifetz, S., Massagué, J., Lindahl, U., and Esko, J. D. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 2267-2271). Here, we show that pgsD mutants contain mutations that either alter GlcA transferase activity selectively or that affect both GlcNAc and GlcA transferase activities. Expression of EXT1 corrects the deficiencies in the mutants, whereas EXT2 and the related EXT-like cDNAs do not. Analysis of the EXT1 mutant alleles revealed clustered missense mutations in a domain that included a (D/E)X(D/E) motif thought to bind the nucleotide sugar from studies of other transferases. These findings provide insight into the location of the GlcA transferase subdomain of the enzyme and indicate that loss of the GlcA transferase domain may be sufficient to cause hereditary multiple exostoses.

* This work was supported by Grants GM33063 (to J. D. E.) and AI36293 (to P. S.) from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ On leave from the Dept. of Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL 35294.

** Present address: Abbott Diagnostics Div., Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6016.

§§ To whom correspondence should be addressed: Dept. of Cellular & Molecular Medicine, CMM-East Rm. 1054, Glycobiology Research and Training Program, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0687. Tel.: 858-822-1100; Fax: 858-534-5611; E-mail: jesko@ucsd.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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