基于三功能探针对蛋白质复合物的深度分析及应用

  蛋白质是生命体中最基本的构建单元，在各种生命活动中扮演着至关重要的角色。受多种翻译后修饰的调控，蛋白质与蛋白质之间产生非共价的相互作用，从而组装为时空动态的蛋白质复合物，并发挥多样的分子功能，实现对表型的精准控制。亲和纯化质谱法是研究蛋白质复合物的经典方法，能直接、无偏地分析细胞裂解液中的蛋白质复合物。然而，该方法难以捕获具有弱相互作用力的瞬时蛋白质复合物。基于三功能探针的化学交联策略在亲和纯化质谱法的基础上，能通过在探针中引入能与蛋白质形成共价键的活性官能团，捕获具有弱相互作用的蛋白质复合物。Photo-pTyr-scaffold是本课题组自主开发的一种结合三功能探针与酪氨酸磷酸化结合结构域SH2结构域的化学蛋白质组学分析策略，具有分析细胞和组织样本中酪氨酸磷酸化介导的蛋白质复合物的能力。但是，该策略所使用的三功能探针不适用于分析其他翻译后修饰介导的蛋白质复合物，并且仍然无法区分富集产物中蛋白质复合物的一一对应关系。因此，本论文主要设计合成了两种新型三功能探针，开发了利用三功能探针分析磷酸化、甲基化等翻译后修饰介导的蛋白质复合物的新型化学蛋白质组学策略。此外，由于受体酪氨酸激酶作为激活细胞信号转导网络的“大门”，是癌症靶向治疗的重要药物靶点之一，本论文将基于三功能探针研究酪氨酸磷酸化蛋白质复合物的方法，应用于对酪氨酸激酶抑制剂筛选。主要的研究内容以及结果总结如下：

       利用谷胱甘肽（Glutathione, GSH）与谷胱甘肽-S-转移酶（Glutathione-S-transferase, GST）之间特异性的非共价作用力，首次设计了一种新型三功能探针，以生物素为富集端，通过GSH标记带GST标签的翻译后修饰识别结构域，利用二苯甲酮共价交联蛋白质复合物。该探针通用地标记了10种带GST标签的磷酸化、甲基化识别结构域。在磷酸化介导的蛋白质复合物的捕获方面，该方法与Photo-pTyr-scaffold的富集效果相当，共同鉴定到了14个表皮生长因子受体EGFR信号通路下游的信号蛋白质。此外，该方法还选择性地富集了4种天然的SH2结构域相关的酪氨酸磷酸化介导的信号蛋白质。对于目前缺乏有效的富集策略的甲基化蛋白质复合物，利用策略也实现了对5个天然甲基化识别结构域的236个相互作用蛋白质的高效富集。本研究以酪氨酸磷酸化与蛋白质甲基化为例，为探索各种翻译后修饰介导的蛋白质复合物提供了一种高通量、高效和通用的化学蛋白质组学分析策略。

       针对Photo-pTyr-scaffold策略无法区分富集产物中蛋白质复合物一一对应关系的问题，本论文进一步开发了一种富集端可断裂的新型三功能探针。该探针能高选择性地捕获10个EGFR信号通路相关的酪氨酸磷酸化信号蛋白质，并经25 mmol/L连二亚硫酸钠处理能高效地断裂富集端，从而实现对富集产物的可控洗脱，为被富集的蛋白质复合物的后续分离提供了可能性。结合适用于分离微量样本的聚丙烯酰胺凝胶电泳（Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, SDS-PAGE）方法，该探针交联的复合物能被分离至高分子量区域进而被质谱检测。基于该方法，在EGFR激活条件下成功地绘制出了20个重要蛋白质的分子量迁移图谱，并在高分子量区域内检测到了形成复合物的低分子量蛋白质，例如泛素连接酶CBL和支架蛋白SHC1。针对CBL和SHC1的蛋白免疫印迹法验证结果与质谱结果一致。该方法在解析酪氨酸磷酸化信号蛋白质复合物一一对应关系的同时，也发现了与EGFR形成复合物的蛋白质占比低的现象，印证了酪氨酸磷酸化化学计量比例低的事实。该策略也解决了用于多对多分析蛋白质复合物一一对应关系的共分馏质谱法和热邻近共聚集法所需样品量大，无法适用于分析微量的酪氨酸磷酸化蛋白质复合物的问题。

       在方法学应用层面，本研究系统地探索了基于三功能探针的Photo-pTyr-scaffold策略用于酪氨酸激酶抑制剂筛选的可行性，开发了基于Photo-pTyr-scaffold策略的筛药平台。研究通过绘制药物靶点蛋白EGFR、肝细胞生长因子受体MET及SHC1对抑制剂厄洛替尼、克唑替尼的剂量响应曲线并计算相应的IC₅₀值，证明了该筛药平台能够定量地评估药物对特定靶点蛋白质的抑制效果。结合质谱检测，该筛药平台也可从组学层面系统地绘制了MET及其10种信号通路下游蛋白质对克唑替尼的剂量响应曲线，证明了该筛药方法同时具有评估药物作用的信号通路的潜力。此外，通过进一步引入酪氨酸磷酸化蛋白质组学分析策略，本研究全局性地展示了在达克替尼、阿法替尼两种EGFR抑制剂的作用下，EGFR信号通路下游的信号蛋白质及其酪氨酸磷酸化位点对药物的剂量响应趋势，探索了药物对下游信号通路产生影响的机制。其中，介导了细胞黏附、迁移等过程的激酶PTK2及其下游蛋白质不受药物影响，而与细胞增殖相关的蛋白质如转录因子STAT5则受药物影响较明显。本研究提供了一种整合蛋白质复合物与磷酸化位点信息分析药物影响的信号通路的功能蛋白质组学分析策略。

Proteins are the most fundamental building blocks of living organisms and play a crucial role in various life activities. Regulated by multiple post-translational modifications (PTMs), proteins interact with each other in a non-covalent manner, thus assembling into spatio-temporally dynamic protein complexes and performing diverse functions for precise control of phenotypes. Affinity purification-mass spectrometry (AP-MS) is a classical method for studying protein complexes, which can directly analyze protein complexes in cell lysates unbiasedly. However, this method has difficulty in capturing transient protein complexes with weak interaction forces. The trifunctional probe-based crosslinking strategy, based on AP-MS, can capture weakly interacting protein complexes by introducing functional groups into the probe that can form covalent bonds with proteins. Photo-pTyr-scaffold is a chemical proteomics strategy that combines a trifunctional probe with the SH2 domain which can binding with pTyr, and can analyze pTyr-mediated protein complexes in cellular and tissue samples. However, the trifunctional probe used in this strategy are not applicable to the analysis of other PTMs-mediated protein complexes and still cannot distinguish the one-to-one correspondence of protein complexes in enriched products. Therefore, this thesis focuses on the design and synthesis of two new trifunctional probes and developing novel chemical proteomics strategies using trifunctional probes to analyse protein complexes mediated by PTMs such as phosphorylation and methylation. In addition, acting as the "gateway" to activate cellular signaling networks, receptor tyrosine kinases (RTKs) are important drug targets for targeted cancer therapy. This thesis applies a trifunctional probe based approach which can study tyrosine phosphorylated protein complexes to the screening of tyrosine kinase inhibitors (TKIs). The main findings and results are summarised below:

This thesis exploits the specific non-covalent interaction between glutathione (GSH) and glutathione-S-transferase (GST) to design a novel trifunctional probe for the first time, using biotin as the enriched group, GSH to label the GST-tagged PTMs-binding domain, and benzophenone to crosslink protein complexes. The probe generically labeled 10 phosphorylated, methylated recognition domains with GST tags. The method is comparable to Photo-pTyr-scaffold in terms of enrichment and 14 epidermal growth factor receptor (EGFR)-downstream signaling proteins were identified via both strategies. Moreover, the method selectively enriched 4 natural SH2 domain-associated tyrosine phosphorylation-mediated signalling proteins. For methylation protein complexes that currently lack an effective enrichment strategy, the method was also utilised to achieve efficient enrichment of 236 interacting proteins from five natural methylation recognition domains. Using tyrosine phosphorylation and protein methylation as an example, the method provides a high-throughput, efficient and versatile chemical proteomics analysis strategy for exploring protein complexes mediated by various PTMs.

To solve the problem that the Photo-pTyr-scaffold strategy cannot distinguish the one-to-one correspondence of protein complexes in the enriched products, a new tri-functional probe with cleavable enrichment ends was further developed in this thesis. The new trifunctional probe with cleavable enrichment end was developed to capture 10 EGFR signalling pathway-associated tyrosine phosphorylation proteins with high selectivity, and with 25 mmol/L Na₂S₂O₄ treatment, the enriched end was efficiently cleaved, enabling controllable elution of the enriched products and providing the possibility of subsequent separation of the enriched protein complexes. In combination with the SDS-PAGE method, which is suitable for the separation of microsamples, the crosslinked complexes can be separated into high molecular weight regions and identified by MS. Co-fractionation mass spectrometry and thermal proximity co-aggregation (TPCA) methods for all-to-all analysis of protein complex one-to-one correspondence require large sample volumes and are not suitable for analysis of trace amounts of pTyr protein complexes. Furthermore, as the trifunctional probe utilizes the strong interaction between biotin and streptavidin to achieve enrichment, the enriched product is difficult to elute from the streptavidin microbeads, creating difficulties for subsequent separation. Based on this method, molecular weight migration profiles of 20 important proteins were successfully mapped under EGFR activation conditions and low molecular weight proteins forming complexes, such as ubiquitin ligase CBL and scaffold protein SHC1, were detected in the high molecular weight region. The validation of the western blot (WB) method against CBL and SHC1 was consistent with the MS results. While resolving the one-to-one correspondence of pTyr signaling protein complexes, the method also revealed a low proportion of proteins forming complexes with EGFR, corroborating the low pTyr stoichiometric ratio. The strategy also solves the problem that co-fractionation mass spectrometry and thermal proximity co-aggregation, which are used for all-to-all analysis of protein complex one-to-one correspondence, require large sample volumes and cannot be applied to the analysis of microscopic tyrosine phosphorylated protein complexes.

As the application of methodology, this study systematically explored the feasibility of the trifunctional probe based Photo-pTyr-scaffold strategy for the screening of TKIs and developed a drug screening platform based on this strategy. By plotting the dose response curves of EGFR, MET and SHC1 to erlotinib and crizotinib and calculating the corresponding IC₅₀ values, the screening platform was demonstrated to quantitatively assess the inhibitory effects of the drugs on specific target proteins. In combination with MS, the screening platform can also systematically map the dose-response curves of MET and its 10 downstream signaling proteins to crizotinib at the proteomic level, demonstrating the potential of the screening approach to assess the signalling pathways on which the drugs act. In addition, by further introducing a tyrosine phosphorylation proteomics analysis strategy, this study globally demonstrated the dose response trends of signalling proteins and their tyrosine phosphorylation sites on the EGFR signalling pathway to the two EGFR inhibitors, dacomitinib and afatinib, and explored the mechanisms by which the drug affects the downstream signalling pathway. Among them, the kinase PTK2 and its downstream proteins, which mediate cell adhesion and migration, were not affected by the drugs, while proteins related to cell proliferation, such as the transcription factor STAT5, were more significantly affected by the drugs. This study provides a functional proteomics analysis strategy that integrates information on protein complexes and phosphorylation sites to analyse inhibitors-affected signalling pathways.

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