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PDBsum entry 2kup
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Signaling protein/oncoprotein
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PDB id
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2kup
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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 nucleophosmin-Anaplastic lymphoma kinase oncoprotein by the phosphotyrosine binding domain of suc1-Associated neurotrophic factor-Induced tyrosine-Phosphorylated target-2.
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Authors
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S.Koshiba,
H.Li,
Y.Motoda,
T.Tomizawa,
T.Kasai,
N.Tochio,
T.Yabuki,
T.Harada,
S.Watanabe,
A.Tanaka,
M.Shirouzu,
T.Kigawa,
T.Yamamoto,
S.Yokoyama.
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Ref.
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J Struct Funct Genomics, 2010,
11,
125-141.
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PubMed id
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Abstract
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The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion oncoprotein,
formed by the t(2;5) chromosomal translocation in anaplastic large-cell
lymphomas, has constitutive tyrosine kinase activity and interacts with a number
of signaling molecules. One of the interacting partners of NPM-ALK is the
adaptor protein, Suc1-associated neurotrophic factor-induced
tyrosine-phosphorylated target (SNT), and mutations that deprive NPM-ALK of all
three of the SNT-binding sites significantly reduced the transforming activity.
In this study, the interactions of the three binding sites in NPM-ALK with the
phosphotyrosine binding (PTB) domain of SNT-2 were analyzed. First, by
isothermal titration calorimetry, we found that the phosphorylation-independent
binding site in NPM-ALK interacts with the SNT-2 PTB domain more tightly than
the phosphorylation-dependent binding sites. Second, the solution structure of
the SNT-2 PTB domain in complex with the nonphosphorylated NPM-ALK peptide was
determined by nuclear magnetic resonance spectroscopy. The NPM-ALK peptide
interacts with the hydrophobic surface of the PTB domain and intermolecularly
extends the PTB beta-sheet. This interaction mode is much broader and more
extensive than those of the phosphorylation-dependent binding sites. Our results
indicate that the higher binding activity of the phosphorylation-independent
binding site is caused by additional hydrophobic interactions.
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