Molecular Insights into the Recruiting Between UCP2 and DDX5/UBAP2L in the Metabolic Plasticity of Non-Small-Cell Lung Cancer
Molecular Insights into the Recruiting Between UCP2 and DDX5/UBAP2L in the Metabolic Plasticity of Non-Small-Cell Lung Cancer
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UCP2 和 DDX5/UBAP2L 在非小细胞肺癌代谢可塑性中招募的分子洞察
DOI：
10.1021/acs.jcim.1c00138
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhang Shengli
中科院分区：
文献类型：
--
作者：
Yang Zhiwei;Li Guoyin;Zhao Yizhen;Zhang Lei;Yuan Xiaohui;Meng Lingjie;Liu Huadong;Han Yong;Jia Lintao;Zhang Shengli
Mitochondrial uncoupling protein 2 (UCP2) is distributed in tumor cells with a link to the support of systemic metabolic deregulation, and the downregulation of UCP2 has been unveiled as a biomarker of oncogenesis and chemoresistance in non-small-cell lung cancer (NSCLC) cells. However, the underlying mechanism of how UCP2 cooperates with other proteins in this metabolic reprogramming remains largely unsolved. We employed a combined computational and experimental strategy to explore into the recruiting of DDX5 with other proteins, and we unraveled the underlying structural mechanisms. We found that recruiting by ATP-dependent RNA helicase DDX5 (DDX5)/ubiquitin-associated protein 2-like (UBAP2L) might help UCP2 to play the pathological roles in NSCLC cells. According to the view of thermodynamics in physics, UCP2 tends to recruit DDX5 rather than UBAP2L, as shown by the ensemble-based docking, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM/GBSA) approach. Cellular immunofluorescence assays further demonstrated that UCP2 associate with DDX5, and the recruiting of DDX5 with UCP2 at least partially contribute to the metabolic plasticity of NSCLCs via the AKT/mTOR pathway. Our study proposed an efficient way for detecting the protein-protein association via the experimentally validated molecular simulation. Our results shed light on the functional annotation of UCP and DDX family proteins in dysregulated metabolism, and the identification of candidate therapeutic targets for NSCLC.
