Solution structure of the first Sam domain of Odin and binding studies with the EphA2 receptor. (Articolo in rivista)

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  • Solution structure of the first Sam domain of Odin and binding studies with the EphA2 receptor. (Articolo in rivista) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/bi300141h (literal)
Alternative label
  • Flavia Anna Mercurio, Daniela Marasco, Luciano Pirone, Emilia Maria Pedone, Maurizio Pellecchia, Marilisa Leone (2012)
    Solution structure of the first Sam domain of Odin and binding studies with the EphA2 receptor.
    in Biochemistry (Easton)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Flavia Anna Mercurio, Daniela Marasco, Luciano Pirone, Emilia Maria Pedone, Maurizio Pellecchia, Marilisa Leone (literal)
Pagina inizio
  • 2136 (literal)
Pagina fine
  • 2145 (literal)
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  • This article has been selected and evaluated by Eileen Lafer, a Member of the Faculty of 1000 (F1000), which places this work in a library of the top 2% of published articles in biology and medicine. http://f1000.com/14257006 Evaluation details: Recommended [6] New Finding, Novel Drug Target Sections: Cell Signalling,Protein Chemistry & Proteomics,Developmental Molecular Mechanisms,Experimental Biophysical Methods,Cell Signalling & Trafficking Structures,Structural Genomics,Biomacromolecule-Ligand Interactions,Protein Folding,Pharmacokinetics & Drug Delivery,Drug Discovery & Design,Cancer Therapeutics Comments: This article is interesting because it combines multiple analytical and biochemical techniques to study protein:protein interactions, to determine binding conformation and to determine dissociation constants for a potential drug target. The Eph receptors are the largest family of receptor tyrosine kinases, and their interactions with ephrin ligands result in various downstream processes {1}. Eph receptor signaling has been linked to embryonic development, specifically axon guidance, cell migration, angiogenesis and segmentation. Recently, overexpression of EphA2 has been associated with various cancers. The endocytosis of EphA2 receptors is a potential target for delivery of drugs or imaging agents directly into tumor cells due to its low expression in most adult tissues. Previous studies have shown that the sterile alpha motif (SAM) domains of Ship2 and Odin (Anks1) are required for regulating endocytosis of EphA2. In this article, Mercurio et al. use liquid-state NMR (nuclear magnetic resonance), SPR (surface plasmon resonance) and ITC (isothemal titration calorimetry) experiments to study the solution structure of the SAM domain from Odin and its binding to the SAM domain of EphA2. NMR chemical shift perturbation mapping indicates that the SAM domains of Odin and EphA2 bind in a manner typical for SAM-SAM complexes, a mid-loop/end-helix interaction. The NMR, SPR and ITC experiments indicate a 1:1 binding stoichiometry between Odin-SAM and EphA2-SAM with dissociation constants in the low micromolar range. These data provide valuable information that could be used to develop novel cancer therapeutics. References: {1} Pasquale EB, Nat Rev Cancer 2010, 10:165-80 [PMID:20179713]. (literal)
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  • 51 (literal)
Rivista
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  • 10 (literal)
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  • 10 (literal)
Note
  • PubMed (literal)
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  • Department of Biological Sciences, University of Naples Federico II, Naples, Italy. Burnham Institute for Medical Research, La Jolla, CA, USA. (literal)
Titolo
  • Solution structure of the first Sam domain of Odin and binding studies with the EphA2 receptor. (literal)
Abstract
  • The EphA2 receptor plays key roles in many physiological and pathological events, including cancer. The process of receptor endocytosis and the consequent degradation have attracted attention as possible means of overcoming the negative outcomes of EphA2 in cancer cells and decreasing tumor malignancy. A recent study indicates that Sam (sterile alpha motif) domains of Odin, a member of the ANKS (ankyrin repeat and sterile alpha motif domain-containing) family of proteins, are important for the regulation of EphA2 endocytosis. Odin contains two tandem Sam domains (Odin-Sam1 and -Sam2). Herein, we report on the nuclear magnetic resonance (NMR) solution structure of Odin-Sam1; through a variety of assays (employing NMR, surface plasmon resonance, and isothermal titration calorimetry techniques), we clearly demonstrate that Odin-Sam1 binds to the Sam domain of EphA2 in the low micromolar range. NMR chemical shift perturbation experiments and molecular modeling studies point out that the two Sam domains interact with a head-to-tail topology characteristic of several Sam-Sam complexes. This binding mode is similar to that we have previously proposed for the association between the Sam domains of the lipid phosphatase Ship2 and EphA2. This work further validates structural elements relevant for the heterotypic Sam-Sam interactions of EphA2 and provides novel insights for the design of potential therapeutic compounds that can modulate receptor endocytosis. (literal)
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