Su Min-Gang, Weng Julia Tzu-Ya, Hsu Justin Bo-Kai, Huang Kai-Yao, Chi Yu-Hsiang, Lee Tzong-Yi
Department of Computer Science and Engineering, Yuan Ze University, Taoyuan, 320, Taiwan.
Department of Medical Research, Taipei Medical University Hospital, Taipei, 110, Taiwan.
BMC Syst Biol. 2017 Dec 21;11(Suppl 7):132. doi: 10.1186/s12918-017-0506-1.
Protein post-translational modification (PTM) plays an essential role in various cellular processes that modulates the physical and chemical properties, folding, conformation, stability and activity of proteins, thereby modifying the functions of proteins. The improved throughput of mass spectrometry (MS) or MS/MS technology has not only brought about a surge in proteome-scale studies, but also contributed to a fruitful list of identified PTMs. However, with the increase in the number of identified PTMs, perhaps the more crucial question is what kind of biological mechanisms these PTMs are involved in. This is particularly important in light of the fact that most protein-based pharmaceuticals deliver their therapeutic effects through some form of PTM. Yet, our understanding is still limited with respect to the local effects and frequency of PTM sites near pharmaceutical binding sites and the interfaces of protein-protein interaction (PPI). Understanding PTM's function is critical to our ability to manipulate the biological mechanisms of protein.
In this study, to understand the regulation of protein functions by PTMs, we mapped 25,835 PTM sites to proteins with available three-dimensional (3D) structural information in the Protein Data Bank (PDB), including 1785 modified PTM sites on the 3D structure. Based on the acquired structural PTM sites, we proposed to use five properties for the structural characterization of PTM substrate sites: the spatial composition of amino acids, residues and side-chain orientations surrounding the PTM substrate sites, as well as the secondary structure, division of acidity and alkaline residues, and solvent-accessible surface area. We further mapped the structural PTM sites to the structures of drug binding and PPI sites, identifying a total of 1917 PTM sites that may affect PPI and 3951 PTM sites associated with drug-target binding. An integrated analytical platform (CruxPTM), with a variety of methods and online molecular docking tools for exploring the structural characteristics of PTMs, is presented. In addition, all tertiary structures of PTM sites on proteins can be visualized using the JSmol program.
Resolving the function of PTM sites is important for understanding the role that proteins play in biological mechanisms. Our work attempted to delineate the structural correlation between PTM sites and PPI or drug-target binding. CurxPTM could help scientists narrow the scope of their PTM research and enhance the efficiency of PTM identification in the face of big proteome data. CruxPTM is now available at http://csb.cse.yzu.edu.tw/CruxPTM/ .
蛋白质翻译后修饰（PTM）在各种细胞过程中发挥着至关重要的作用，它能调节蛋白质的物理和化学性质、折叠、构象、稳定性及活性，进而改变蛋白质的功能。质谱（MS）或串联质谱（MS/MS）技术通量的提高，不仅推动了蛋白质组规模研究的激增，也促成了大量已鉴定的PTM。然而，随着已鉴定PTM数量的增加，或许更关键的问题是这些PTM参与了何种生物学机制。鉴于大多数基于蛋白质的药物通过某种形式的PTM发挥治疗作用，这一点尤为重要。然而，我们对于药物结合位点及蛋白质-蛋白质相互作用（PPI）界面附近PTM位点的局部效应和频率的理解仍然有限。了解PTM的功能对于我们操控蛋白质生物学机制的能力至关重要。
在本研究中，为了解PTM对蛋白质功能的调控，我们将25835个PTM位点映射到蛋白质数据银行（PDB）中具有可用三维（3D）结构信息的蛋白质上，其中包括3D结构上的1785个修饰PTM位点。基于获取的结构PTM位点，我们提出使用五个属性对PTM底物位点进行结构表征：PTM底物位点周围氨基酸的空间组成、残基和侧链方向，以及二级结构、酸性和碱性残基的划分和溶剂可及表面积。我们进一步将结构PTM位点映射到药物结合和PPI位点的结构上，共识别出1917个可能影响PPI的PTM位点和3951个与药物-靶点结合相关的PTM位点。本文介绍了一个集成分析平台（CruxPTM），它具有多种用于探索PTM结构特征的方法和在线分子对接工具。此外，蛋白质上PTM位点的所有三级结构都可以使用JSmol程序进行可视化。
解析PTM位点的功能对于理解蛋白质在生物学机制中所起的作用很重要。我们的工作试图描绘PTM位点与PPI或药物-靶点结合之间的结构关联。面对庞大的蛋白质组数据，CruxPTM可以帮助科学家缩小其PTM研究范围并提高PTM鉴定效率。CruxPTM现已在http://csb.cse.yzu.edu.tw/CruxPTM/ 上线。
