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Structural insights into the Notch-modifying glycosyltransferase Fringe

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Abstract

Fringe proteins are β1,3-N-acetylglucosaminyltransferases that modify Notch receptors, altering their ligand-binding specificity to regulate Notch signaling in development. We present the crystal structure of mouse Manic Fringe bound to UDP and manganese. The structure reveals amino acid residues involved in recognition of donor substrates and catalysis, and a putative binding pocket for acceptor substrates. Mutations of several invariant residues in this pocket impair Fringe activity in vivo.

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Figure 1: Overall view of the catalytic domain of murine Manic Fringe (Mfng) in complex with UDP and Mn2+.
Figure 2: Substrate recognition by Manic Fringe.

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Acknowledgements

We thank D. Lindner, A.-M. Lawrence and E. Loeser for technical assistance, A. Scholz and J. Basquin for crystal screening, M. Walsh at the European Synchrotron Radiation Facility BM14 beamline and the staff at the Swiss Light Source for assistance with data collection, M. Hothorn for crystallographic advice and P. Brick, A. Cook and E. Lorentzen for critical reading of the manuscript. This work was supported by the Human Frontier Science Program (RGP0063/2002-C).

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Authors and Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, D-69117, Germany

    Martin Jinek, Ya-Wen Chen, Stephen M Cohen & Elena Conti

  2. Institute of Medical Biochemistry and Genetics, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen, DK-2200, Denmark

    Henrik Clausen

  3. Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, D-82152, Germany

    Elena Conti

Authors
  1. Martin Jinek
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  2. Ya-Wen Chen
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  3. Henrik Clausen
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  4. Stephen M Cohen
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  5. Elena Conti
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Corresponding authors

Correspondence to Stephen M Cohen or Elena Conti.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

UDP binding in the active site of MFNG. (PDF 98 kb)

Supplementary Fig. 2

Sequence alignment of Fringe orthologs. (PDF 401 kb)

Supplementary Table 1

Data collection and refinement statistics. (PDF 66 kb)

Supplementary Methods (PDF 118 kb)

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Jinek, M., Chen, YW., Clausen, H. et al. Structural insights into the Notch-modifying glycosyltransferase Fringe. Nat Struct Mol Biol 13, 945–946 (2006). https://doi.org/10.1038/nsmb1144

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  • DOI: https://doi.org/10.1038/nsmb1144

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