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PDBsum entry 1r1s
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Peptide binding protein
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PDB id
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1r1s
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for differential recognition of tyrosine-Phosphorylated sites in the linker for activation of t cells (lat) by the adaptor gads.
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Authors
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S.Cho,
C.A.Velikovsky,
C.P.Swaminathan,
J.C.Houtman,
L.E.Samelson,
R.A.Mariuzza.
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Ref.
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EMBO J, 2004,
23,
1441-1451.
[DOI no: ]
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PubMed id
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Abstract
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The transmembrane protein, linker for activation of T cells (LAT), is essential
for T-cell activation and development. Phosphorylation of LAT at multiple
tyrosines creates binding sites for the adaptors Gads and Grb2, leading to
nucleation of multiprotein signaling complexes. Human LAT contains five
potential binding sites for Gads, of which only those at Tyr171 and Tyr191
appear necessary for T-cell function. We asked whether Gads binds preferentially
to these sites, as differential recognition could assist in assembling defined
LAT-based complexes. Measured calorimetrically, Gads-SH2 binds LAT tyrosine
phosphorylation sites 171 and 191 with higher affinities than the other sites,
with the differences ranging from only several fold weaker binding to no
detectable interaction. Crystal structures of Gads-SH2 complexed with
phosphopeptides representing sites 171, 191 and 226 were determined to 1.8-1.9 A
resolutions. The structures reveal the basis for preferential recognition of
specific LAT sites by Gads, as well as for the relatively greater promiscuity of
the related adaptor Grb2, whose binding also requires asparagine at position +2
C-terminal to the phosphorylated tyrosine.
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Figure 6.
Figure 6 Ribbon diagrams of Gads-SH2 and Grb2 structures. (A)
Gads-SH2 in complex with pLAT171. (B) Gads-SH2 in complex with
pLAT191. (C) Gads-SH2 in complex with pLAT226. (D) Grb2-SH2 in
complex with KPFpYVNV (PDB entry code 1tze) (Rahuel et al,
1996). Secondary structure elements are labeled following the
nomenclature for Lck-SH2 (Eck et al, 1993), and are colored as
follows:  -helices,
red and yellow;  -strands,
green; and loop regions, gold. The N- and C-termini are labeled.
The bound peptides are silver, with side chain oxygen and
nitrogen atoms colored red and blue, respectively, and
phosphorus atoms green.
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Figure 8.
Figure 8 Stereo images of Gads-SH2 and Grb2-SH2 structures. (A)
View of the +1 binding site in the Gads-SH2/pLAT226 complex.
Relevant stretches of the Gads-SH2 polypeptide backbone are
cream; labels identify side chains and bound waters (red balls)
in the vicinity of +1 Glu of pLAT226 (silver). The side chain of
the modeled +1 His residue is green. (B) The +1 binding site in
the Grb2-SH2/KPFpYVNV complex (PDB entry code 1tze) (Rahuel et
al, 1996). The Grb2-SH2 polypeptide backbone is cream. Side
chains and waters (red balls) in the vicinity of +1 Glu of the
bound peptide (silver) are labeled; the modeled +1 His is green.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2004,
23,
1441-1451)
copyright 2004.
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