Mohammadpour Hemn, Pourfathollah Ali Akbar, Nikougoftar Zarif Mahin, Khalili Saeed
Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
J Theor Biol. 2016 Mar 21;393:98-104. doi: 10.1016/j.jtbi.2015.12.029. Epub 2016 Jan 15.
Dkk3 is a member of Dkk family proteins, regulating Wnt signaling. Dkk3 plays different roles in human and mouse tumors. Dkk3 predominantly act as a tumor suppressor, however several reports revealed that Dkk3 could accelerate cancer cell proliferation. Herein, we aimed at launching an in silico study to determine Dkk3 structure and its interactions with Kremen and LRP as Wnt signaling receptors as well as EGF receptor. Using various softwares a model was built for Dkk3 molecule. Different protein modeling approaches along with model refinement processes were employed to arrive at the final model. To achieve the final complex of Dkk3 with Kremen, LRP and EGFR molecules protein-protein docking servers were employed. Model assessment softwares indicated the high quality of the finally refined Dkk3 3D structure, indicating the accuracy of modeling and refinement process. Our results revealed that Dkk3 is capable of interacting with Kremen, LRP and EGFR with comparable binding energies. Dkk3 efficiently interacts with LRP, Kremen and EGF receptor and may be a promising protein in cancer therapy by blocking Wnt and EGFR downstream signaling.
Dkk3是Dkk家族蛋白的成员之一，可调节Wnt信号传导。Dkk3在人类和小鼠肿瘤中发挥着不同作用。Dkk3主要作为一种肿瘤抑制因子，然而一些报告显示Dkk3可加速癌细胞增殖。在此，我们旨在开展一项计算机模拟研究，以确定Dkk3的结构及其与作为Wnt信号受体的Kremen和LRP以及表皮生长因子受体（EGF受体）之间的相互作用。我们使用各种软件构建了Dkk3分子的模型。采用了不同的蛋白质建模方法以及模型优化过程来得到最终模型。为了获得Dkk3与Kremen、LRP和EGFR分子的最终复合物，我们使用了蛋白质-蛋白质对接服务器。模型评估软件表明最终优化后的Dkk3三维结构质量很高，这表明建模和优化过程的准确性。我们的结果显示，Dkk3能够以相当的结合能与Kremen、LRP和EGFR相互作用。Dkk3能有效地与LRP、Kremen和EGF受体相互作用，通过阻断Wnt和EGFR下游信号传导，它可能是癌症治疗中一种有前景的蛋白质。
