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J Biol Chem, Vol. 274, Issue 15, 9946-9954, April 9, 1999

Dynamic Epigenetic Regulation of Initial O-Glycosylation by UDP-N-Acetylgalactosamine:Peptide N-Acetylgalactosaminyltransferases
SITE-SPECIFIC GLYCOSYLATION OF MUC1 REPEAT PEPTIDE INFLUENCES THE SUBSTRATE QUALITIES AT ADJACENT OR DISTANT SER/THR POSITIONS

Franz-Georg Hanisch, Stefan Müller, Helle Hassan^¶, Henrik Clausen^¶, Natasha Zachara, Andrew A. Gooley, Hans Paulsen^**, Kim Alving, and Jasna Peter-Katalinic

From the  Institute of Biochemistry, University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany, the ^¶ Department of Oral Diagnostics, School of Dentistry, University of Copenhagen, DK2200 Copenhagen, Denmark, the  Macquarie Center for Analytical Biotechnology, Macquarie University, Sydney NSW 2109, Australia, the ^** Institute of Organic Chemistry, University of Hamburg, 20146 Hamburg, Germany, and the  Institute of Medical Physics and Biophysics, University of Münster, 48149 Münster, Germany.

In search of possible epigenetic regulatory mechanisms ruling the initiation of O-glycosylation by polypeptide:N-acetylgalactosaminyltransferases, we studied the influences of mono- and disaccharide substituents of glycopeptide substrates on the site-specific in vitro addition of N-acetylgalactosamine (GalNAc) residues by recombinant GalNAc-Ts (rGalNAc-T1, -T2, and -T3). The substrates were 20-mers (HGV20) or 21-mers (AHG21) of the MUC1 tandem repeat peptide carrying GalNAc or Gal1-3GalNAc at different positions. The enzymatic products were analyzed by MALDI mass spectrometry and Edman degradation for the number and sites of incorporated GalNAc. Disaccharide placed on the first position of the diad Ser-16-Thr-17 prevents glycosylation of the second, whereas disaccharide on the second position of Ser-16-Thr-17 and Thr-5-Ser-6 does not prevent GalNAc addition to the first. Multiple disaccharide substituents suppress any further glycosylation at the remaining sites. Glycosylation of Ser-16 is negatively affected by glycosylation at position 6 (Thr-10) or 10 (Ser-6) and is inhibited by disaccharide at position 11 (Thr-5), suggesting the occurrence of glycosylation-induced effects on distant acceptor sites. Kinetic studies revealed the accelerated addition of GalNAc to Ser-16 adjacent to GalNAc-substituted Thr-17, demonstrating positive regulatory effects induced by glycosylation on the monosaccharide level. These antagonistic effects of mono- and disaccharides could underlie a postulated regulatory mechanism.

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

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