Vincenzi Marian, Mercurio Flavia Anna, Autiero Ida, Leone Marilisa
Institute of Biostructures and Bioimaging, Via Pietro Castellino 111, 80131 Naples, Italy.
Molecules. 2024 Feb 27;29(5):1024. doi: 10.3390/molecules29051024.
The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)-Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2-Sam and Ship2-Sam reciprocal binding interfaces. Next, potential differences in the chemical-physical properties of mutant and wild-type Sam domains were evaluated by bioinformatics tools based on analyses of primary sequences. Three-dimensional (3D) structural models of mutated EphA2-Sam and Ship2-Sam domains were built as well and deeply analysed with diverse computational instruments, including molecular dynamics, to classify potentially stabilizing and destabilizing mutations. In the end, the influence of mutations on the EphA2-Sam/Ship2-Sam interaction was studied through docking techniques. This in silico approach contributes to understanding, at the molecular level, the mutation/cancer relationship by predicting if amino acid substitutions could modulate EphA2 receptor endocytosis.
脂质磷酸酶Ship2通过形成异型Sam（无活性α基序）-Sam复合物与EphA2受体相互作用。Ship2作为受体内吞作用及后续降解的负调控因子，抑制其与EphA2的结合可诱导癌细胞产生抗癌作用。本文提出一种计算方法，以研究Ship2-Sam/EphA2-Sam相互作用与癌症发生及进一步发展之间的关系。首先通过COSMIC（癌症体细胞突变目录）数据库进行搜索，以识别位于EphA2-Sam和Ship2-Sam相互结合界面内部或附近的癌症相关错义突变。接下来，基于对一级序列的分析，利用生物信息学工具评估突变型和野生型Sam结构域化学物理性质的潜在差异。还构建了突变型EphA2-Sam和Ship2-Sam结构域的三维（3D）结构模型，并使用包括分子动力学在内的各种计算工具进行深入分析，以分类潜在的稳定和不稳定突变。最后，通过对接技术研究突变对EphA2-Sam/Ship2-Sam相互作用的影响。这种计算机模拟方法有助于在分子水平上理解突变/癌症关系，预测氨基酸替换是否可调节EphA2受体内吞作用。
