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PDBsum entry 2vj2
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Protein binding
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PDB id
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2vj2
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References listed in PDB file
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Key reference
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Title
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A conserved face of the jagged/serrate dsl domain is involved in notch trans-Activation and cis-Inhibition.
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Authors
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J.Cordle,
S.Johnson,
J.Z.Tay,
P.Roversi,
M.B.Wilkin,
B.H.De madrid,
H.Shimizu,
S.Jensen,
P.Whiteman,
B.Jin,
C.Redfield,
M.Baron,
S.M.Lea,
P.A.Handford.
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Ref.
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Nat Struct Biol, 2008,
15,
849-857.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
97%.
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Abstract
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The Notch receptor and its ligands are key components in a core metazoan
signaling pathway that regulates the spatial patterning, timing and outcome of
many cell-fate decisions. Ligands contain a disulfide-rich Delta/Serrate/LAG-2
(DSL) domain required for Notch trans-activation or cis-inhibition. Here we
report the X-ray structure of a receptor binding region of a Notch ligand, the
DSL-EGF3 domains of human Jagged-1 (J-1(DSL-EGF3)). The structure reveals a
highly conserved face of the DSL domain, and we show, by functional analysis of
Drosophila melanogster ligand mutants, that this surface is required for both
cis- and trans-regulatory interactions with Notch. We also identify, using NMR,
a surface of Notch-1 involved in J-1(DSL-EGF3) binding. Our data imply that cis-
and trans-regulation may occur through the formation of structurally distinct
complexes that, unexpectedly, involve the same surfaces on both ligand and
receptor.
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Figure 2.
(a) The overall structure of J-1[DSL-EGF3] is shown in a
cartoon representation colored from blue at the N terminus
(residue 187) to red at the C terminus (residue 335). Disulfide
bonds are shown in yellow stick representations, and two views
differing by a rotation of 90° about the long axis are
shown. (b) Stereo view of the DSL domain fold. (c) Sequences of
the four J-1[DSL-EGF3] domains with disulfide bond pairings
indicated. (d) Crystallographic structure of N-1[11–13] shown
as in a. The bound Ca^2+ in each EGF domain is shown in a
space-filling representation. All structural figures were
generated with PyMol (http://www.pymol.org/).
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Figure 3.
Analysis of an alignment of the Jagged/Delta family DSL
domains representing various species (H. sapiens Jagged-1,
residues 187–229; D. melanogaster Serrate, residues 237–279;
H. sapiens Jagged-2, residues 198–240; H. sapiens Delta-like
1, residues 179–221; D. melanogaster Delta, residues
184–226; H. sapiens Delta-like 4, residues 175–217; C.
elegans LAG-2, residues 124–166; H. sapiens Delta-like 3,
residues 178–215) (a) and the DSL structure (b) reveals a
series of highly conserved, but surface-exposed, residues.
Residues that are conserved and predicted to form a Notch
binding face are shown in red, cysteines in yellow and a
nonconserved residue on the opposite face in blue. (c)
Electrostatic surface potential of J-1[DSL-EGF3] and
N-1[11–13] plotted at  4
kT e^-1 using APBS^54. Note the positively charged patch (blue)
within the DSL domain of Jagged-1 and the negatively charged
surface (red) of Notch. The surfaces predicted by
sequence/structure analysis (J-1[DSL-EGF3]) and NMR studies
(N-1[11–13]) to be involved in binding are highlighted by
green bands.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nat Struct Biol
(2008,
15,
849-857)
copyright 2008.
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