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PDBsum entry 4cue
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Transcription
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PDB id
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4cue
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References listed in PDB file
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Key reference
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Title
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Fringe-Mediated extension of o-Linked fucose in the ligand-Binding region of notch1 increases binding to mammalian notch ligands.
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Authors
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P.Taylor,
H.Takeuchi,
D.Sheppard,
C.Chillakuri,
S.M.Lea,
R.S.Haltiwanger,
P.A.Handford.
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Ref.
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Proc Natl Acad Sci U S A, 2014,
111,
7290-7295.
[DOI no: ]
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PubMed id
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Abstract
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The Notch signaling pathway is essential for many aspects of development, cell
fate determination, and tissue homeostasis. Notch signaling can be modulated by
posttranslational modifications to the Notch receptor, which are known to alter
both ligand binding and receptor activation. We have modified the ligand-binding
region (EGF domains 11-13) of human Notch1 (hN1) with O-fucose and O-glucose
glycans and shown by flow cytometry and surface plasmon resonance that the
Fringe-catalyzed addition of GlcNAc to the O-fucose at T466 in EGF12
substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We
have subsequently determined the crystal structures of EGF domains 11-13 of hN1
modified with either the O-fucose monosaccharide or the GlcNAc-fucose
disaccharide at T466 of EGF12 and observed no change in backbone structure for
each variant. Collectively, these data demonstrate a role for GlcNAc in
modulating the ligand-binding site in hN1 EGF12, resulting in an increased
affinity of this region for ligands Jagged1 and DLL1. We propose that this
finding explains the Fringe-catalyzed enhancement of Notch-Delta signaling
observed in flies and humans, but suggest that the inhibitory effect of Fringe
on Jagged/Serrate mediated signaling involves other regions of Notch.
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