Solution Structure of the First Sam Domain of Odin and Binding Studies with the EphA2 Receptor(870 views) Mercurio FA, Marasco D, Pirone L, Pedone E, Pellecchia M, Leone M
Biochemistry (ISSN: 0006-2960, 1520-4995, 1520-4995electronic), 2012 Mar 13; 51(10): 2136-2145.
Keywords: Ankyrin, Binding Modes, Binding Studies, Cancer Cells, Isothermal Titration Calorimetry, Micromolar Range, Molecular Modeling Studies, Nmr Chemical Shift Perturbations, Receptor Endocytosis, Solution Structures, Structural Elements, Therapeutic Compounds, Topology Characteristics, Binding Energy, Molecular Biology, Ephrin Receptor A2, Phosphatase, Protein Odin, Protein Ship2, Unclassified Drug, Amino Acid Sequence, Article, Binding Kinetics, Carbon Nuclear Magnetic Resonance, Heteronuclear Single Quantum Coherence, Molecular Docking, Molecular Interaction, Nitrogen Nuclear Magnetic Resonance, Nuclear Overhauser Effect, Priority Journal, Protein Domain, Protein Structure, Receptor Binding, Sterile Alpha Motif Domain, Surface Plasmon Resonance, Adaptor Proteins, Signal Transducing, Humans, Multiprotein Complexes, Biomolecular, Protein Interaction Domains And Motifs, Recombinant Proteins, Thermodynamics,
Affiliations: *** IBB - CNR ***
Department of Biological Sciences, University of Naples Federico II, Naples, Italy
Centro Interuniversitario di Ricerca sui Peptidi Bioattivi (CIRPEB), Naples, Italy
Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy
Sanford-Burnham Medical Research Institute, San Diego, CA 92037, United States
References: Not available.
Solution Structure of the First Sam Domain of Odin and Binding Studies with the EphA2 Receptor
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.
Solution Structure of the First Sam Domain of Odin and Binding Studies with the EphA2 Receptor