title: 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.
abstract: 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.
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Seizo
authors.initials: S
authors.lastname: Koshiba
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Yoko
authors.initials: Y
authors.lastname: Motoda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tomizawa
authors.forename: Takuma
authors.initials: T
authors.lastname: Kasai
authors.forename: Naoya
authors.initials: N
authors.lastname: Tochio
authors.forename: Takashi
authors.initials: T
authors.lastname: Yabuki
authors.forename: Takushi
authors.initials: T
authors.lastname: Harada
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Takanori
authors.initials: T
authors.lastname: Kigawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010446:Peptide Fragments; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010446:Peptide Fragments; D019000:Phosphotyrosine; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases
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