我們發展了一套利用特殊化學修飾的金奈米粒子作為親和性分離細胞中大型蛋白質複合體的新穎探針。利用這項技術來全面性的標定出與雌激素應答序列相關的轉錄活化複合體，此方法命名為針對蛋白質複合體的定量奈米質譜學(QNanoPX)。此策略中我們將修飾上聚乙二醇以及雌激素應答序列的金奈米粒子當作正探針，而把只修飾上聚乙二醇而未修飾雌激素應答序列的金奈米粒子作為負探針，皆是利用硫醇自組裝單分子層的方法將分子與金奈米做共價鍵結。金奈米正探針有非常高的抵抗非專一性吸附蛋白的能力以及很高的分散性，且由實驗結果得知，它分離純化待測蛋白的能力比一般傳統使用的膠體粒子好二十倍。除此之外，金奈米粒子單純只用表面分子與待測物作用，所以可用來分離的蛋白複合體大小不會受限，不像膠體粒子是有孔徑的，因此太大的蛋白複合體會無法進入孔徑中作用，而且在分離過程一些雜蛋白也有可能會擴散進孔徑中被困住而造成過高的背景訊號。此親和性純化的方法同時結合了定量質譜學及統計學來揭露乳癌細胞內會與雌激素應答序列作用的蛋白複合體之組成、以及鑑定複合體中會受雌激素存在而調控的蛋白種類。結果顯示，被金奈米正探針純化下來的蛋白絕大多數都是透過有意義的作用力，而且包括雌激素接受器阿法在內的將近一半的蛋白當受到雌激素二十四小時刺激後會被些微的影響。將結果用生物資訊和路徑分析的方法剖析後發現，大多數受調控的蛋白不只受雌激素接受器阿法的轉錄調節、也跟c-Myc有關。進一步的研究證實，雌激素會使c-Myc和雌激素應答序列的作用力增強十四倍，這也代表c-Myc和雌激素接受器阿法在雌激素調控的轉錄行為中扮演著很重要的角色。總而言之，我們的研究結果證明了此針對蛋白質複合體的定量奈米質譜學方法可成功的應用在蛋白路徑的研究，也可進一步揭開轉錄因子相互作用的重要性。

We developed an integrated proteomics approach using a chemically functionalized gold nanoparticle (AuNP) as a novel probe for affinity purification in order to analyze a large protein complex in vivo. We then applied this approach to globally map the transcriptional activation complex of the estrogen response element (ERE). This approach was designated as Quantitative Nano-Proteomics for Protein complexes (QNanoPX). In this approach, the positive AuNP-ERE probes were functionalized with polyethylene glycol (PEG) and the consensus sequence of ERE and negative AuNP-PEG probes were functionalized with PEG without the ERE via thiolated self-assembly monolayer (SAM) technique. The AuNP-ERE probe had substantially low nonspecific binding and high solubility, which resulted in a 20-fold enrichment of the factor compared to gel beads. In addition, the surface-only binding allows the probe to capture a large protein complex without any restrictions due to pore size. The affinity purification method was combined with MS-based quantitative proteomics and statistical methods to reveal the components of the ERE complex in MCF-7 cells and to identify those components within the complex that were altered by the presence of 17-estradiol (E2). Results indicated that a majority of proteins pulled down by the positive probe exhibited significant binding, and approximately one-half of the proteins, including estrogen receptor  (ER), were slightly but significantly affected by a 24-h treatment with E2. Based on a combination of bioinformatic and pathway analysis, most of the affected proteins, however, appeared to be related to the transcriptional regulation of not only ER, but also c-Myc. Further confirmation indicated that E2 enhanced the ERE binding of c-Myc by 14-fold, which indicated that c-Myc may play a major role, along with ER, in E2-mediated transcription. Taken together, our results demonstrated a successful QNanoPX approach towards pathway discovery and further revealed the importance of cross-interactions among transcription factors.

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