Biswas Ria, Ghosh Semanti, Bagchi Angshuman
Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, Nadia, India.
J Mol Recognit. 2017 Nov;30(11). doi: 10.1002/jmr.2643. Epub 2017 Jun 14.
Metastatic melanoma is the most fatal type of skin cancer. The roles of matrix metalloproteinases (MMPs) have well been established in the onset of melanoma. Basigin (BSG) belongs to the immunoglobulin superfamily and is critical for induction of extracellular MMPs during the onset of various cancers including melanoma. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3-ligase that interacts with BSG and mediates its membrane localization, which leads to MMP expression in melanoma cells. This makes TRAF6 a potential therapeutic target in melanoma. We here conducted protein-protein interaction studies on TRAF6 and BSG to get molecular level insights of the reactions. The structure of human BSG was constructed by protein threading. Molecular-docking method was applied to develop the TRAF6-BSG complex. The refined docked complex was further optimized by molecular dynamics simulations. Results from binding free energy, surface properties, and electrostatic interaction analysis indicate that Lys340 and Glu417 of TRAF6 play as the anchor residues in the protein interaction interface. The current study will be helpful in designing specific modulators of TRAF6 to control melanoma metastasis.
转移性黑色素瘤是最致命的皮肤癌类型。基质金属蛋白酶（MMPs）在黑色素瘤发病过程中的作用已得到充分证实。基底膜蛋白（BSG）属于免疫球蛋白超家族，在包括黑色素瘤在内的各种癌症发病过程中，对细胞外MMPs的诱导至关重要。肿瘤坏死因子受体相关因子6（TRAF6）是一种E3连接酶，它与BSG相互作用并介导其膜定位，从而导致黑色素瘤细胞中MMP的表达。这使得TRAF6成为黑色素瘤潜在的治疗靶点。我们在此对TRAF6和BSG进行了蛋白质-蛋白质相互作用研究，以获得反应的分子水平见解。通过蛋白质穿线构建了人BSG的结构。应用分子对接方法构建TRAF6-BSG复合物。通过分子动力学模拟对优化后的对接复合物进行进一步优化。结合自由能、表面性质和静电相互作用分析结果表明，TRAF6的Lys340和Glu417在蛋白质相互作用界面中起锚定残基的作用。本研究将有助于设计TRAF6的特异性调节剂以控制黑色素瘤转移。
