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PDBsum entry 4jmh
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De novo protein
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PDB id
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4jmh
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References listed in PDB file
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Key reference
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Title
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Directed network wiring identifies a key protein interaction in embryonic stem cell differentiation.
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Authors
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N.Yasui,
G.M.Findlay,
G.D.Gish,
M.S.Hsiung,
J.Huang,
M.Tucholska,
L.Taylor,
L.Smith,
W.C.Boldridge,
A.Koide,
T.Pawson,
S.Koide.
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Ref.
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Mol Cell, 2014,
54,
1034-1041.
[DOI no: ]
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PubMed id
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Abstract
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Cell signaling depends on dynamic protein-protein interaction (PPI) networks,
often assembled through modular domains each interacting with multiple peptide
motifs. This complexity raises a conceptual challenge, namely to define whether
a particular cellular response requires assembly of the complete PPI network of
interest or can be driven by a specific interaction. To address this issue, we
designed variants of the Grb2 SH2 domain ("pY-clamps") whose
specificity is highly biased toward a single phosphotyrosine (pY) motif among
many potential pYXNX Grb2-binding sites. Surprisingly, directing Grb2
predominantly to a single pY site of the Ptpn11/Shp2 phosphatase, but not other
sites tested, was sufficient for differentiation of the essential primitive
endoderm lineage from embryonic stem cells. Our data suggest that discrete
connections within complex PPI networks can underpin regulation of particular
biological events. We propose that this directed wiring approach will be of
general utility in functionally annotating specific PPIs.
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