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J. Biol. Chem., Vol. 280, Issue 34, 30158-30165, August 26, 2005

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Regions of Drosophila Notch That Contribute to Ligand Binding and the Modulatory Influence of Fringe^*

Aiguo Xu, Liang Lei, and Kenneth D. Irvine

From the Howard Hughes Medical Institute, the Waksman Institute, and the Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854

Two glycosyltransferases that transfer sugars to epidermal growth factor (EGF) domains, OFUT1 and Fringe, regulate Notch signaling. To characterize the impact of glycosylation at the 23 consensus O-fucose sites in Drosophila Notch, we conducted deletion mapping and site-specific mutagenesis and then assayed the binding of soluble forms of Notch to cell-surface ligands. Our results support the conclusion that EGF11 and EGF12 are essential for ligand binding, but indicate that other EGF domains also make substantial contributions to ligand binding. Characterization of Notch deletion constructs and O-fucose site mutants further revealed that no single site or region can account for the influence of Fringe on Notch-ligand binding. Additionally, we observed an influence of Fringe on a Notch fragment including only 4 of its 36 EGF domains (EGF10–13). Together, our observations imply that glycosylation influences Notch-ligand interactions through a distributive mechanism that involves local interactions with multiple EGF domains and led us to suggest a structural model for how Notch interacts with its ligands.

Received for publication, May 20, 2005 , and in revised form, June 24, 2005.

^* This work was supported by the Howard Hughes Medical Institute and by National Institutes of Health Grant R01-GM54594 (to K. D. I.). 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.

Present address: Dept. of Biological Sciences, Columbia University, New York, NY 10027.

To whom correspondence should be addressed: Waksman Inst., Rutgers University, 190 Frellinghuysen Rd., Piscataway, NY 08854. Tel.: 732-445-2332; Fax: 732-445-7431; E-mail: irvine{at}waksman.rutgers.edu.

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