Leone Marilisa, Cellitti Jason, Pellecchia Maurizio
Burnham Institute for Medical Research, La Jolla, California, USA.
Biochemistry. 2008 Dec 2;47(48):12721-8. doi: 10.1021/bi801713f.
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.
无菌α基序（Sam）结构域是蛋白质相互作用模块，主要通过同二聚化和异二聚化参与许多生物学过程。最近有报道称，脂质磷酸酶Ship2调节EphA2受体的内吞作用，这一过程已被研究作为降低肿瘤恶性程度的可能途径。一种异型Sam-Sam结构域相互作用介导了这一过程。在这里，我们报告了对Ship2的Sam结构域的核磁共振（NMR）和等温滴定量热法（ITC）研究，揭示了其三维结构以及与EphA2受体的Sam结构域可能的相互作用模式。这些研究还确定了Ship2的一个最小肽区域，该区域对EphA2受体的Sam结构域保留结合亲和力。因此，这种肽以及对EphA2受体内吞作用重要的关键结构元件的检测为开发具有潜在抗癌活性的新型小分子拮抗剂提供了可能的途径。
