摘要
本论文针对后修饰蛋白质组学研究中磷酸化蛋白质和糖基化蛋白质质谱分析所面临的特异性富集和检测灵敏度等热点难点问题,将多种技术手段,包括纳米技术、化学衍生、信号放大等,与传统的蛋白质分析方法相结合,开展了一系列的研究工作,发展了与之相关的质谱鉴定新技术和新方法,并取得了实际应用方面的成功,获得了一些创新性的研究成果。文章主要内容和所取得的主要研究成果摘要如下：
第一章概述了质谱鉴定前处理技术对于蛋白质组学研究的意义所在和其中存在的主要问题,对于近年来所发展的各种低丰度蛋白质预富集新技术新方法分门别类的进行了细致的归纳总结。分析了磷酸化蛋白质组学和糖基化蛋白质组学研究中所面临的主要困难,并按照各种富集方法所采用的原理进行了分类并一作了详细的阐述。此外,针对纳米技术在蛋白质富集中的应用展开了综述,对于不同种类的纳米材料富集低丰度肽段/蛋白质的方法分类进行了总结,并归纳了后修饰蛋白质组学中纳米材料富集方法的特点且作了详尽的阐述。最后,提出了本论文选题的目的和意义所在。
第二章针对翻译后修饰蛋白质组学研究中磷酸化肽段的质谱鉴定问题,发展了基于羧基衍生反应增强磷酸化多肽电子转移解离(ETD)质谱分析的新策略。由于ETD质谱在使肽段裂解的同时能够保留肽链上的后修饰信息,对于磷酸化蛋白质组学来说,采用ETD质谱分析磷酸化肽段具有巨大的潜力。然而,ETD质谱只适用于带两个或两个以上电荷的肽段,而在蛋白质组学研究中通常采用胰蛋白酶酶解的磷酸化肽段在电喷雾质谱中较一般的胰酶酶解肽段更难带上多电荷,这就限制了ETD质谱技术对于磷酸化位点的分析。采用本研究中的策略,肽段上所有的羧基基团,包括C端和肽链上酸性氨基酸残基上的羧基,与衍生试剂1-(2-嘧啶基)哌嗪(PP)反应从而带上化学标签。衍生标记后的磷酸化肽段的电荷态大幅度增加,此时再使用ETD质谱对其进行分析就显示出衍生标记的优势所在：在电喷雾离子源中电离时主要以单电荷分子离子形式存在的肽段原本并不能够使用ETD质谱进行分析,然而经过羧基衍生处理后,其电荷态有所增加,这时就能采用ETD裂解技术就能得到该肽段丰富的串联质谱图信息。此外,PP衍生技术还能提高二氧化钛富集法的特异性。这是因为衍生反应封闭了肽段上的羧基基团,从而消除了羧基与二氧化钛之间的相互作用,因此减少了富集过程中的非特异性吸附,提高了富集效率。衍生后的磷酸化肽段在反相液相色谱柱中的保留时间也有所增加,克服了某些磷酸化肽段在传统的反相液相色谱中难以分离的困难。
第三章针对翻译后修饰蛋白质组学研究中糖基化肽段／蛋白质的分离富集问题,合成了具有核-卫星结构的功能纳米复合材料,并以此新型材料为基础发展了新的糖基化肽段／蛋白质富集方法,将其成功地应用于人类大肠癌第三期临床组织样本的N-糖基化位点的分析鉴定中。糖基化蛋白质的天然含量非常低,再加上由于糖链结构的复杂性使得每个可能发生糖基化修饰的位点上又存在微相上的不均一性,因此对于糖基化肽段／蛋白质进行质谱分析前处理非常必要。到目前为止,所发展的各类富集方法都有其固有的缺点。由于糖蛋白质组学研究的需要,急需发展更为简单灵敏且适用性广的富集新方法。近年来,纳米技术的飞速发展使其被广泛的应用于各种生物样品的分离分析研究中,而其中纳米复合材料因为集合了各种材料本身独有的特性,能够发挥出更大的优势,使得研究者们对于复合材料的关注度日益增加。本研究中合成的新型纳米复合材料由二氧化硅包裹的铁磁核心和修饰在磁核上的大量纳米金颗粒组成。其中,高质量的磁性纳米材料通过水热反应得到,其粒径分布十分均匀。随后,我们采用溶胶-凝胶法将正硅酸乙酯水解浓缩产生的二氧化硅沉积到Fe304磁珠表面,形成由薄层二氧化硅包裹的磁性纳米颗粒。本章研究中所用到的纳米金是采用柠檬酸钠还原法制备得到的。每个纳米金颗粒表面通过自组装修饰上大量的有机长链,在其链末端共价键合上能跟糖链特异性结合的硼酸官能团。这些有机长链的存在既可以降低被材料捕获的目标分子之间的空间位阻效应,又可以抑制材料表面的非特异性吸附。因此,在此基础上发展的糖基化蛋白质分离富集方法简单有效,具有很好的特异性,适用于浓度极低的糖基化肽段／蛋白质。该方法的富集特异性不论是在对标准糖基化蛋白质的选择性富集还是在胰蛋白酶酶解产物的富集中都得到了证实。实验结果表明,每克材料的吸附容量达到约79 mg辣根过氧化物酶蛋白,远高于同类型的商品化磁珠。对于所富集到的肽段／蛋白质,只需使用磁铁就能将其从溶液体系中分离,根据样品复杂程度进行清洗后,加入酸性的洗脱液即可将目标肽段／蛋白质从材料上洗脱下来。采用我们发展的这种富集技术,所得到的糖基化肽段和糖基化蛋白质的回收率分别能达到85.9%和71.6%。当将此富集方法应用于分析人类大肠癌组织样品的N-糖基化位点时,共鉴定到155个非冗余糖基化蛋白质上的194个N-糖基化位点,其中165个位点都是以前文献没有报道过的,占85.1%。
第四章针对翻译后修饰蛋白质组学研究中糖基化蛋白质的质谱检测问题,发展了一种采用硼酸修饰磁珠分离糖基化蛋白质后对之进行纳米金标记,从而将糖基化蛋白质的质谱信号转化成纳米金的质谱信号的高灵敏度的质谱检测方法。使用MALDI质谱直接检测纳米金时可以得到强度很高的Au2+的峰,其背景噪音几乎可以忽略,因此选择纳米金粒子作为质谱信号报告分子非常理想。由于每个纳米金粒子包含超过64000个金原子,因此采用纳米金检测时的Au2+信号替代糖基化蛋白质的质谱信号的方法从理论上来讲能够将信号强度放大好几个数量级。在本章研究中,我们使用硼酸修饰的磁珠将糖基化蛋白质从溶液中分离后,通过将纳米金粒子表面修饰的羧基与蛋白质上游离氨基的反应将其共价键合于蛋白质肽链上。然后,再用酸性洗脱液将标记有纳米金的糖基化蛋白质从磁珠上释放,重新进入溶液体系,最后进行MALDI质谱分析,检测Au2+的信号。实验结果表明,采用这种信号放大的策略,对于辣根过氧化物酶的检测限可以降至7.695 fM(S/N=3),而对另外两种标准糖基化蛋白质——去唾液酸胎球蛋白和核糖核酸酶B的检测限也能降至18.87 fM(S/N=3)和322.2 fM(S/N=3)。
第五章针对糖基化翻译后修饰蛋白质组学研究中的肼化学分离富集方法存在的问题,合成了氨基修饰的磁性纳米颗粒,并以此材料为基础发展了富集糖基化多肽的方法,同时对于富集流程进行了初步的优化。肼化学富集法的适用范围非常广,无论是N-糖基化蛋白质还是O-糖基化蛋白质,其糖链经氧化后都可以通过肼腙反应对之进行富集。然而,酰肼基具有强还原性,且极易水解生成肼,由于肼的毒性较大,因此在操作时需要特别小心。本章研究中则以更稳定更温和的氨基修饰磁性纳米颗粒为基础发展了同样适用范围较广的糖基化多肽富集法：首先使用强氧化剂高碘酸钠,将糖链上的羟基氧化成醛基,通过活泼的醛基与氨基之间的反应将糖基化多肽固体到磁珠上,选择合适的清洗缓冲溶液反复清洗材料,除去表面非特异性吸附的肽段,最后使用肽N-糖苷酶F (PNGase F)对磁珠上的糖基化多肽进行去糖基化处理后将其从材料上释放,最终进行质谱分析。我们对于富集流程中的清洗步骤进行了详细的优化考察,确定了最优清洗条件,实现了对于标准糖基化蛋白质酶解产物中糖基化多肽的特异性富集。
总之,本论文围绕翻译后修饰蛋白质组学研究中磷酸化蛋白质和糖基化蛋白质特异性富集和质谱鉴定方面的热点难点问题,以多种技术手段为基础,以发展相关的蛋白质组学研究新技术新方法并进行实际的应用研究为目标,建立了将化学衍生标记应用于质谱分析的策略,合成了适用于不同研究目的的新型功能纳米材料,为解决翻译后修饰蛋白质组学中磷酸化肽段质谱鉴定、糖基化蛋白质特异性富集及信号放大等问题提供了新颖有效的研究手段和方法。
Based on proteome research background and development trend of nanomaterials, the research interest of this work focused on combining various techniques, including nanotechnology, chemical derivatization, signal amplification etc., with traditional bioanalytical methods in proteome research, to develop a series of novel techniques and methods to resolve existing problems in specific enrichment and mass spectrometric detection of phosphorylated proteins and glycosylated proteins in post-translational proteome research. This dissertation is divided into five parts.
Chapter 1 summarized current situation and existing problems of pretreatment technologies prior to mass spectrometric analysis in proteomics, key advances in the development of low-abundance protein enrichment and preconcentration techniques. Since phosphorylation and glycosylation are both highly important post-translational modifications and key challenge in phosphorproteome and glycoproteome research is the development of fast and effective enrichment strategies for high-throughput identification, we highlighted several examples on various types of enrichment methods that have been utilized to specifically capture these modified proteins for subsequent mass spectrometric analysis. In the past few years, the introduction of nanoparticles into proteome research has accelerated the development of enrichment methods, so we also summarized recent developments of using different functional nanomaterials for pre-concentration of low-abundance peptides/proteins, including those containing post-translational modifications, such as phosphorylation and glycosylation, prior to mass spectrometric analysis in details. The intention and meaning of this dissertation were explained in this chapter.
In chapter 2, a novel strategy based on carboxy group derivatization is presented for specific characterization of phosphopeptides. Electron-transfer dissociation (ETD), a relatively new dissociation method that was developed recently, has the attractive feature of independence of amide bond protonation and shows the advantage in preserving the information about post-translational modifications during peptide fragmentation, thus providing an efficient way for sequencing phosphorylated peptides/proteins. However, since ETD only works with peptides having more than one positive charge, one of the most challenging tasks posed in phosphorylation analysis is to increase ion charge state. By tagging the carboxy group with 1-(2-pyrimidyl) piperazine (PP), the ion charge states of phosphopeptides can be largely enhanced, showing great advantages for sequencing phosphorylated peptides with electron-transfer dissociation MS. For peptides that mainly hold one positive charge from electrospray ion source, they are not suited for ETD-MS/MS analysis. However, after PP-derivatization, the primary species became those who hold double charges. Thus, it was not a barrier anymore for them to be applied to ETD-MS/MS analysis. Besides, by blocking the carboxy group, the PP-derivatization method can also be employed to eliminate non-specific interactions between acidic residues and TiO2, which is the major competitive process during the TiO2-based phosphorylated peptides/proteins enrichment strategy, thus greatly increasing the selectivity toward phosphopeptides/phosphoproteins. Moreover, being tagged with a hydrophobic group, the retention time of phosphopeptides in RPLC can be prolonged, overcoming the difficulty of separating phosphopeptides in RPLC-based approach. Together with several other advantages, such as ease of handling, rapid reaction time, broad applicability and good reproducibility, this PP-derivatization method is promising for high-throughput phosphoproteome research.
In chapter 3, a core-satellite-structured composite material has been successfully synthesized for capturing glycosylated peptides or proteins. The inherent low abundance of glycoproteins and the microheterogeneity of each glycosylation site make the enrichment procedure before MS analysis a prerequisite. Although a variety of methods are available for glycopeptides or glycoprotein enrichment, the complete mapping of glycoproteome is still a challenging task. Nanoparticles are attracting considerable interest on account of their significant potential in biotechnology and biomedicine for diagnostic and therapeutic applications. Recently, particular attention has been paid to the synthesis of composite nanoparticles that have both the biocompatibility and surface chemistry of gold and the magnetic properties of superparamagnetic particles. The novel hybrid material synthesized in our study is composed of a silicacoated ferrite "core" and numerous "satellites" of gold nanoparticles with lots of "anchors". The anchor,3-aminophenylboronic acid, designed for capturing target molecules, is highly specific toward glycosylated species. The long organic chains bridging the gold surface and the anchors could reduce the steric hindrance among the bound molecules and suppress nonspecific bindings. Due to the excellent structure of the current material, the trap-and-release enrichment of glycosylated samples is quite simple, specific, and effective. Indeed, the composite nanoparticles could be used for enriching glycosylated peptides and proteins with very low concentrations, and the enriched samples can be easily separated from bulk solution by a magnet. By using this strategy, the recovery of glycopeptides and glycoproteins after enrichment were found to be 85.9 and 71.6% separately, whereas the adsorption capacity of the composite nanoparticles was proven to be more than 79 mg of glycoproteins per gram of the material. Moreover, the new composite nanoparticles were applied to enrich glycosylated proteins from human colorectal cancer tissues for identification of N-glycosylation sites. In all,194 unique glycosylation sites mapped to 155 different glycoproteins have been identified, of which 165 sites (85.1%) were newly identified.
Chapter 4 presents a highly sensitive glycoprotein detection method, by using magnetic microparticle to isolate glycoproteins and gold nanoparticle (AuNP) to amplify the signal intensity with mass spectrometer. The homemade AuNP is a perfect signal reporter since it gives intensive peak of Au2+ and negligible background noise with mass spectrometer. Additionally, each AuNP contains more than 64000 gold atoms so it is potentially capable of amplifying the signal intensity for several orders of magnitude once adopting Au2+ as the signal tag instead of detecting intact glycoproteins. To fulfill this purpose, carboxy group functionalized AuNP was graft onto amino groups of glycoproteins after isolating glycoproteins with boronic acid functionalized magnetic microparticles. The AuNPs bound glycoproteins were then eluted and applied to mass spectrometer. Using this strategy, the limit of detection (LOD) of horseradish peroxidase was improved to 7.695 fM (S/N=3) while that for another two glycoproteins (asialofetuin and ribonuclease b) were 18.87 fM (S/N=3) and 322.2 fM (S/N=3) respectively. Moreover, this method shows good selectivity encountering glycans and non-glycoproteins.
In chapter 5, amine modified magnetic nanoparticles were synthesized and applied to selectively enrich glycosylated peptides from tryptic glycoprotein digestion. In this strategy, glycoproteins are digested into peptides firstly, containing both glycosylated peptides and nonglycosylated peptides. Then, the cis-diol groups of carbohydrates in glycopeptides are oxidized into aldehydes, which can form covalent bonds with amine groups immobilized on magnetic nanoparticles. Non-glycosylated peptides are washed away, whereas the glycosylated peptides still remain on the matrix material. PNGase F is then used to release the N-glycopeptides and the resulting peptides are subjected to mass spectrometric analysis. The washing buffer and washing condition are carefully optimized in this study. Finally, we realized selective enrichment of glycopeptides from tryptic digests of standard glycoproteins.
In summary, the main contribution of this dissertation is to develop and provide several effective techniques and methods to resolve the difficulties in specific enrichment and mass spectrometric detection of phosphorylated proteins and glycosylated proteins. Several functional nanomaterials have been synthesized for different research requirements, and novel technologies have been introduced into proteome research fields. We aim at exploring and finding out new techniques in the pre-concentration and MS analysis of phosphorylated and glycosylated proteins, so that more breakthroughs can be obtained in post-translational proteome research.
引文
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