SERPIN STRUCTURE AND FUNCTION

丝氨酸超家族是一大类中等大小(约45 60 kDa)的蛋白质，它们有一个共同的三维折叠，代表蛋白质的亚稳定构象。尽管有共同的三倍体，但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、促进轴突生长的能力、调节肿瘤侵袭、参与细胞分化和调节细胞凋亡。该计划项目的长期目标是了解亚稳定的丝氨酸折叠在正常和病理功能中的亚稳折叠途径和后果，并在赋予给定的丝氨酸的特殊性质时，(Ii)能够经历构象变化但不能抑制蛋白酶(甲状腺激素结合球蛋白)或(Iii)既不起抑制作用也不似乎经历丝氨酸构象变化(血管紧张素)。本提案代表了对关于蛇纹针结构和功能的一些最重要的悬而未决的问题的一致重视。该方案由四个项目组成，涉及这一目标的不同方面。这些研究包括丝氨酸和半胱氨酸蛋白酶抑制机制的性质的结构以及蛇毒如何能够动态地捕获与蛋白酶的复合体(项目2，Steven Olson，P.I.)，为什么非抑制的蛇体血管紧张素原和甲状腺激素结合球蛋白仍然需要蛇针折叠(项目3，Phillip Patston，P.I.)，以及蛇毒及其与蛋白酶和特定配体的络合物的X射线结构(项目4，Karl Volz，P.I.)。有三个核心，由管理核心、分子生物学和细胞培养核心、蛋白质表达和纯化核心组成。所有四个项目都将使用这三个核心。该项目代表着跨部门和跨学院的合作，涉及伊利诺伊大学芝加哥分校四个系和两个学院的研究人员，以及一群国际公认的合作调查人员。

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.