Mass Spectrometry-Based Protein Footprinting for Higher-Order Structure Analysis: Fundamentals and Applications.
Mass Spectrometry-Based Protein Footprinting for Higher-Order Structure Analysis: Fundamentals and Applications.
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DOI：
10.1021/acs.chemrev.9b00815
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发表时间：
2020-05-27
期刊：
影响因子：
62.1
通讯作者：
Gross ML
中科院分区：
文献类型：
--
作者：
Liu XR;Zhang MM;Gross ML
蛋白质采用不同的高级结构（HOS）来实现其独特的生物学功能。了解蛋白质高阶结构和动力学的复杂性需要综合方法，其中质谱（MS）现在定位于发挥关键作用。其中一种方法是蛋白质足迹。虽然足迹法最初的证明是用于蛋白质/核酸键合的HOS测定，但该概念后来被应用于基于MS的蛋白质HOS分析，通过该分析，不同的共价标记方法“标记”蛋白质的溶剂可及表面积（SASA）以反映蛋白质HOS。氢氘交换（HDX），其中D2 O中的氘取代骨架酰胺的氢，是足迹法的最常见实例。其优点是足迹反映SASA和氢键，而一个方法的缺点是标记是可逆的。另一种是通过具有高特异性的靶向试剂对氨基酸侧链上的官能团进行缓慢不可逆标记，探测选定位点的结构变化。第三种足迹方法是通过与快速、不可逆的标记物质的反应，所述标记物质具有高度反应性，并且在亚毫秒的时间尺度上广泛地足迹几个氨基酸链。所有这些共价标记方法联合收割机构成了一个解决问题的工具箱，以质谱作为测量工具的HOS说明。由于其高通量能力，快速可用性和高空间分辨率，学术界和工业界对基于MS的蛋白质足迹的需求越来越大，我们对这些共价标记方法的历史，描述，原理，机制和应用进行了总结。此外，根据它们可以回答的生物学问题，突出了它们的应用。这篇评论的目的是作为一个教程MS为基础的蛋白质HOS的阐明，并作为一个参考研究人员寻求一个MS为基础的工具，以解决蛋白质科学中的问题。
Proteins adopt different higher order structures (HOS) to enable their unique biological functions. Understanding the complexities of protein higher order structures and dynamics requires integrated approaches, where mass spectrometry (MS) is now positioned to play a key role. One of those approaches is protein footprinting. Although the initial demonstration of footprinting was for the HOS determination of protein/nucleic acid bonding, the concept was later adapted to MS-based protein HOS analysis, through which different covalent labeling approaches “mark” the solvent accessible surface area (SASA) of proteins to reflect protein HOS. Hydrogen deuterium exchange (HDX), where deuterium in D2O replaces hydrogen of the backbone amides, is the most common example of footprinting. Its advantage is the footprint reflects SASA and hydrogen bonding, whereas one method drawback is the labeling is reversible. Another is slow irreversible labeling of functional groups on amino-acid side chains by targeted reagents with high specificity, probing structural changes at selected sites. A third footprinting approach is by reactions with fast, irreversible labeling species that are highly reactive and footprint broadly several amino-acid chains on the time scale of sub-milliseconds. All these covalent labeling approaches combine to constitute a problem-solving toolbox that takes mass spectrometry as the measurement tool for HOS elucidation. As there has been a growing need for MS-based protein footprinting in both academia and industry owing to its high throughput capability, prompt availability, and high spatial resolution, we present a summary of the history, descriptions, principles, mechanisms, and applications of these covalent labeling approaches. Moreover, their applications are highlighted according to the biological questions they can answer. This review is intended as a tutorial for MS-based protein HOS elucidation and as a reference for investigators seeking a MS-based tool to address questions in protein science.
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