SERPIN STRUCTURE AND FUNCTION

serpin超家族是一大群中等大小的蛋白质（约45 60kDa），具有共同的三维折叠，代表蛋白质的亚稳构象。尽管有常见的三级褶皱，丝氨酸或半胱氨酸蛋白酶的抑制、甲状腺激素的血液运输、血管活性激素血管紧张素的血液生成、神经突生长促进能力、肿瘤侵袭调节、参与细胞分化和细胞凋亡调节。该项目的长期目标是了解亚稳折叠途径和亚稳蛇形蛋白折叠对正常和病理功能的影响，以及在赋予给定蛇形蛋白的特定特性时，是否（抗凝血酶，α 1蛋白酶抑制剂和crmA），（ii）能够发生构象变化，但没有抑制蛋白酶（甲状腺素结合球蛋白）的能力；（iii）既不作为抑制剂起作用，也不表现出发生丝氨酸蛋白构象变化（血管紧张素）。本提案是对serpin结构和功能方面一些最重要的悬而未决的问题的一致关注。该计划包括四个项目，以解决这一目标的不同方面。研究包括丝氨酸和半胱氨酸蛋白酶的抑制机制的本质结构，蛇形蛋白如何能够动态捕获与蛋白酶的复合物（项目2，Steven Olson， P.I.），为什么蛇形蛋白的非抑制性血管紧张素原和甲状腺素结合球蛋白仍然需要蛇形蛋白折叠（项目3，Phillip Patston， P.I.），蛇形蛋白及其与蛋白酶和特定配体的复合物的x射线结构（项目4，Karl Volz， P.I.）。pi)。有三个核心组成的行政核心，一个分子生物学和细胞培养核心，一个蛋白质表达和纯化核心。所有四个项目都将使用这三个核心。该项目代表了伊利诺伊大学芝加哥分校四个系和两个学院的研究人员以及一组国际公认的合作研究人员的跨部门和跨学院合作。

The serpin superfamily is a large group of medium-size proteins (approximately 45 60kDa) that have a common three-dimensional fold that represents a metastable conformation of the protein. Despite the common tertiary fold, inhibition of serine or cysteine proteinases, blood transport of thyroid hormones, blood generation of the vasoactive hormone angiotensin, neurite-outgrowth-promoting-ability, regulation of tumor invasion, involvement in cellular differentiation and regulation of apoptosis. The long term goal of this program project is to understand the metastable folding pathway and consequences of the metastable serpin fold both for normal and pathological function, and in conferring the particular properties of a given serpin, whether the (anti-thrombin, alpha1-proteinase inhibitor, and crmA), (ii) is able to undergo conformational change but without the ability to inhibit proteinase (thyroxine binding globulin) or (iii) acts neither as an inhibitor nor appears to undergo the serpin conformational change (angiotensin). The present proposal represents a concerted attach on some of the most important outstanding questions on serpin structure and function. The program comprises four projects that address different aspects of this goal. Studies include those on the structure of the nature of the inhibition mechanism of both serine and cysteine proteinases and how serpins are able to kinetically trap complexes with proteinase (Project 2, Steven Olson, P.I.), why the serpin fold should still be needed for the non- inhibitory serpins angiotensinogen and thyroxine binding globulin (Project 3, Phillip Patston, P.I.), and the x-ray structures of serpins and their complexes with proteinases and specific ligands (Project 4, Karl Volz, P.I.). There are three cores consisting of an administrative core, a molecular biology and cell culture core, and a protein expression and purification core. All three cores will be used by all four projects. The project represents an inter-departmental and inter-college collaboration, involving investigators in four departments and two colleges of the University of Illinois at Chicago as well as a group of internationally- recognized collaborating investigators.