Nygaard Mads, Terkelsen Thilde, Vidas Olsen André, Sora Valentina, Salamanca Viloria Juan, Rizza Fabio, Bergstrand-Poulsen Sanne, Di Marco Miriam, Vistesen Mette, Tiberti Matteo, Lambrughi Matteo, Jäättelä Marja, Kallunki Tuula, Papaleo Elena
Computational Biology Laboratory and Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center Copenhagen, Denmark.
Department of Biomedical Sciences, University of Padua Padua, Italy.
Front Mol Biosci. 2016 Dec 15;3:78. doi: 10.3389/fmolb.2016.00078. eCollection 2016.
SCAN domains in zinc-finger transcription factors are crucial mediators of protein-protein interactions. Up to 240 SCAN-domain encoding genes have been identified throughout the human genome. These include cancer-related genes, such as the myeloid zinc finger 1 (), an oncogenic transcription factor involved in the progression of many solid cancers. The mechanisms by which SCAN homo- and heterodimers assemble and how they alter the transcriptional activity of zinc-finger transcription factors in cancer and other diseases remain to be investigated. Here, we provide the first description of the conformational ensemble of the MZF1 SCAN domain cross-validated against NMR experimental data, which are probes of structure and dynamics on different timescales. We investigated the protein-protein interaction network of MZF1 and how it is perturbed in different cancer types by the analyses of high-throughput proteomics and RNASeq data. Collectively, we integrated many computational approaches, ranging from simple empirical energy functions to all-atom microsecond molecular dynamics simulations and network analyses to unravel the effects of cancer-related substitutions in relation to MZF1 structure and interactions.
锌指转录因子中的SCAN结构域是蛋白质-蛋白质相互作用的关键介质。在整个人类基因组中已鉴定出多达240个编码SCAN结构域的基因。这些基因包括与癌症相关的基因，如髓系锌指1（MZF1），它是一种致癌转录因子，参与多种实体癌的进展。SCAN同二聚体和异二聚体组装的机制以及它们如何改变癌症和其他疾病中锌指转录因子的转录活性仍有待研究。在这里，我们首次描述了MZF1 SCAN结构域的构象集合，并根据NMR实验数据进行了交叉验证，NMR实验数据是不同时间尺度上结构和动力学的探针。我们通过高通量蛋白质组学和RNA测序数据分析了MZF1的蛋白质-蛋白质相互作用网络以及它在不同癌症类型中是如何受到干扰的。我们综合了许多计算方法，从简单的经验能量函数到全原子微秒分子动力学模拟和网络分析，以揭示癌症相关替代对MZF1结构和相互作用的影响。
