title: NMR studies of a heterotypic Sam-Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 receptor.
abstract: Sterile alpha motif (Sam) domains are protein interaction modules that are implicated in many biological processes mainly via homo- and heterodimerization. It has been recently reported that the lipid phosphatase Ship2 regulates endocytosis of the EphA2 receptor, a process that has been investigated as a possible route to reduce tumor malignancy. A heterotypic Sam-Sam domain interaction is mediating this process. Here, we report NMR and ITC (isothermal titration calorimetry) studies on the Sam domain of Ship2 revealing its three-dimensional structure and its possible mode of interaction with the Sam domain from the EphA2 receptor. These studies have also resulted in the identification of a minimal peptide region of Ship2 that retains binding affinity for the Sam domain of the EphA2 receptor. Hence, this peptide and the detection of key structural elements important for EphA2 receptor endocytosis provide possible ways for the development of novel small molecule antagonists with potential anticancer activity.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California, USA.
authors.forename: Marilisa
authors.initials: M
authors.lastname: Leone
authors.forename: Jason
authors.initials: J
authors.lastname: Cellitti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D002151:Calorimetry; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D036104:Receptor, EphA2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D036104:Receptor, EphA2; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases