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Originally published In Press as doi:10.1074/jbc.M205851200 on October 22, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49850-49862, December 20, 2002
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Mucin Core O-Glycosylation Is Modulated by Neighboring Residue Glycosylation Status
KINETIC MODELING OF THE SITE-SPECIFIC GLYCOSYLATION OF THE APO-PORCINE SUBMAXILLARY MUCIN TANDEM REPEAT BY UDP-GalNAc:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASES T1 AND T2*,

Thomas A. GerkenDagger §, Jiexin ZhangDagger , Jessica Levine, and Åke Elhammer

From the Departments of Pediatrics and Biochemistry, W. A. Bernbaum Center for Cystic Fibrosis Research and University Hospitals Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and  Pharmacia Corporation, Kalamazoo, Michigan 49001

The influence of peptide sequence and environment on the initiation and elongation of mucin O-glycosylation is not well understood. The in vivo glycosylation pattern of the porcine submaxillary gland mucin (PSM) tandem repeat containing 31 O-glycosylation sites (Gerken, T. A., Gilmore, M., and Zhang, J. (2002) J. Biol. Chem. 277, 7736-7751) reveals a weak inverse correlation with hydroxyamino acid density (and by inference the density of glycosylation) with the extent of GalNAc glycosylation and core-1 substitution. We now report the time course of the in vitro glycosylation of the apoPSM tandem repeat by recombinant UDP-GalNAc:polypeptide alpha -GalNAc transferases (ppGalNAc transferase) T1 and T2 that confirm these findings. A wide range of glycosylation rates are found, with several residues showing apparent plateaus in glycosylation. An adjustable kinetic model that reduces the first-order rate constants proportional to neighboring glycosylation status, plus or minus three residues of the site of glycosylation, was found to reasonably reproduce the experimental rate data for both transferases, including apparent plateaus in glycosylation. The unique, transferase-specific, positional weighting constants reveal information on the peptide/glycopeptide recognition site for each transferase. Both transferases displayed high sensitivities to neighboring Ser/Thr glycosylation, whereas ppGalNAc T2 displayed additional high sensitivities to the presence of nonglycosylated Ser/Thr residues. This is the first demonstration of the ability to model mucin O-glycosylation kinetics, confirming that under the appropriate conditions neighboring glycosylation status can be a significant factor modulating the first step of mucin O-glycan biosynthesis.

* This work was supported by NCI Grant RO1-CA-78834 from the National Institutes of Health (to T. A. G.).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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Methods and Results, Supplemental Tables 1 and 2, and Supplemental Fig. S1-S8.

Dagger Both authors contributed equally to this work.

§ To whom correspondence should be addressed: Dept. of Pediatrics, Case Western Reserve University School of Medicine. BRB, 2109 Adelbert Rd., Cleveland, OH 44106-4948. Tel. 216-368-4556; Fax: 216-368-4223; E-mail: txg2@po.cwru.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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