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PDBsum entry 3nmw
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Cell adhesion/cell cycle
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PDB id
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3nmw
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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 the recognition of asef by adenomatous polyposis coli.
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Authors
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Z.Zhang,
L.Chen,
L.Gao,
K.Lin,
L.Zhu,
Y.Lu,
X.Shi,
Y.Gao,
J.Zhou,
P.Xu,
J.Zhang,
G.Wu.
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Ref.
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Cell Res, 2012,
22,
372-386.
[DOI no: ]
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PubMed id
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Abstract
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Adenomatous polyposis coli (APC) regulates cell-cell adhesion and cell migration
through activating the APC-stimulated guanine nucleotide-exchange factor (GEF;
Asef), which is usually autoinhibited through the binding between its Src
homology 3 (SH3) and Dbl homology (DH) domains. The APC-activated Asef
stimulates the small GTPase Cdc42, which leads to decreased cell-cell adherence
and enhanced cell migration. In colorectal cancers, truncated APC constitutively
activates Asef and promotes cancer cell migration and angiogenesis. Here, we
report crystal structures of the human APC/Asef complex. We find that the
armadillo repeat domain of APC uses a highly conserved surface groove to
recognize the APC-binding region (ABR) of Asef, conformation of which changes
dramatically upon binding to APC. Key residues on APC and Asef for the complex
formation were mutated and their importance was demonstrated by binding and
activity assays. Structural superimposition of the APC/Asef complex with
autoinhibited Asef suggests that the binding between APC and Asef might create a
steric clash between Asef-DH domain and APC, which possibly leads to a
conformational change in Asef that stimulates its GEF activity. Our structures
thus elucidate the molecular mechanism of Asef recognition by APC, as well as
provide a potential target for pharmaceutical intervention against cancers.
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