前体蛋白加工酶furin的天然抑制剂及相互作用蛋白研究
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摘要
多肽或蛋白质以前体形式合成后,需要前体加工酶的剪切加工才能获得完全的生物活性。Furin是发现得最早且功能研究最为清楚的哺乳动物前体加工酶,许多重要的生理过程需要furin的参与,如多肽与蛋白质激素的合成与分泌、膜受体的成熟、血浆蛋白前体的激活等;同时多种疾病的发生也与furin密切相关,如病毒外壳蛋白和细菌外毒素的加工活化以及肿瘤的转移等。尽管十几年来人们通过基因工程改造和多肽库筛选等方法得到了一些有效的furin抑制剂,但其天然抑制剂一直未曾找到;另外,虽然对furin的细胞内定位和自身加工成熟有较多研究,但很多具体机制和细节并不清楚。因此,对furin天然抑制剂的寻找和进一步改造以及对furin相互作用蛋白质的鉴定和功能分析不仅具有重要的理论意义,也有利于开发抗病毒和抗细菌外毒素的先导药物。本研究采用蛋白纯化的方法从猪肝脏组织中纯化到三个具有强抑制活力的furin抑制剂并鉴定为组蛋白H1的C-端不同长度的片段,通过位点改造得到保持抑制活性的14肽抑制剂,为进一步面向临床的开发研究提供实验依据。同时表明组蛋白H1与furin相互作用并参与了furin体内活性的调节。此外,通过对接头蛋白mint3与furin相互作用的研究发现mint3调控了furin在高尔基体的定位;通过蛋白质组学的方法分析了furin P结构域相互作用的蛋白,并初步确定了NMMHC-A通过结合该结构域促进了furin的成熟。
本论文可分为两个部分,第一部分为furin抑制剂研究,包括furin天然抑制剂的纯化及改造(第一章)和组蛋白H1参与furin体内活性调节(第二章);第二部分为furin相互作用蛋白研究,包括mint3与furin的相互作用调控了furin的高尔基体定位(第三章)和furin的P结构域相互作用蛋白质的分析(第四章)。
After biosynthesis, peptides and proteins are often activated by intracellular limited proteolysis by proprotein convertases (PCs). Furin is the first identified mammalian PC and the most extensively studied member of the known PCs. Furin play important roles in various biological events such as the activation and secretion of peptide and protein hormones, the maturation of membrane receptors and the activation of plasma proteins. Furin is also involved in many diseases such as the activation of viral glycoproteins and bacterial exotoxins and the metastasis of cancer. Although synthetic and bioengineered inhibitors of furin have been well characterized, its endogenous inhibitor has not been directly purified from mammalian tissue to date. On the other hand, though a few associated proteins of furin were identified and extensively studied in the past years, whether other binding proteins exist and what roles they play in the regulation of furin localization and maturation are still unclear. Searching for and functional investigation of endogenous inhibitors and partners of furin is not only helpful to undestand the function of furin in vivo, but also to develop anti-viral and anti-bacterial drugs. In this study, three potent inhibitors of furin were purified from porcine liver by using biochemical methods and identified to be the C-terminal fragments of histnone H1 with different sizes. Furthermore, we demonstrated that a 14 amino acid peptide of histnone H1 around the reactive site was a potent inhibitor of furin, which will be useful for further drug design, and histone H1 regulated furin activity in vivo. In addition, our results about the associated proteins of furin showed that mint3 interacted with the cytoplasmic domain of furin and regulated the TGN localization of furin, and NMMHC-A participated in the maturation of furin through binding P domain of furin.
This dissertation is consisted of two major parts: one part focuses on the endogenous inhibitor of furin (chapter 1: purification and optimization of endogenous inhibitors of furin and chapter 2: histone H1 regulates furin activity in vivo), and the other part is about the associated proteins of furin including mint3 that regulates the localization of furin (chapter 3) and nonmuscle myosin type A heavy chain that regulates the maturation of furin (chapter 4).
本论文可分为两个部分,第一部分为furin抑制剂研究,包括furin天然抑制剂的纯化及改造(第一章)和组蛋白H1参与furin体内活性调节(第二章);第二部分为furin相互作用蛋白研究,包括mint3与furin的相互作用调控了furin的高尔基体定位(第三章)和furin的P结构域相互作用蛋白质的分析(第四章)。
After biosynthesis, peptides and proteins are often activated by intracellular limited proteolysis by proprotein convertases (PCs). Furin is the first identified mammalian PC and the most extensively studied member of the known PCs. Furin play important roles in various biological events such as the activation and secretion of peptide and protein hormones, the maturation of membrane receptors and the activation of plasma proteins. Furin is also involved in many diseases such as the activation of viral glycoproteins and bacterial exotoxins and the metastasis of cancer. Although synthetic and bioengineered inhibitors of furin have been well characterized, its endogenous inhibitor has not been directly purified from mammalian tissue to date. On the other hand, though a few associated proteins of furin were identified and extensively studied in the past years, whether other binding proteins exist and what roles they play in the regulation of furin localization and maturation are still unclear. Searching for and functional investigation of endogenous inhibitors and partners of furin is not only helpful to undestand the function of furin in vivo, but also to develop anti-viral and anti-bacterial drugs. In this study, three potent inhibitors of furin were purified from porcine liver by using biochemical methods and identified to be the C-terminal fragments of histnone H1 with different sizes. Furthermore, we demonstrated that a 14 amino acid peptide of histnone H1 around the reactive site was a potent inhibitor of furin, which will be useful for further drug design, and histone H1 regulated furin activity in vivo. In addition, our results about the associated proteins of furin showed that mint3 interacted with the cytoplasmic domain of furin and regulated the TGN localization of furin, and NMMHC-A participated in the maturation of furin through binding P domain of furin.
This dissertation is consisted of two major parts: one part focuses on the endogenous inhibitor of furin (chapter 1: purification and optimization of endogenous inhibitors of furin and chapter 2: histone H1 regulates furin activity in vivo), and the other part is about the associated proteins of furin including mint3 that regulates the localization of furin (chapter 3) and nonmuscle myosin type A heavy chain that regulates the maturation of furin (chapter 4).
引文
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