SERPIN STRUCTURE AND FUNCTION

丝氨酸蛋白酶抑制剂超家族是一大群中等大小的蛋白质（约45 - 60 kDa），它们具有共同的三维折叠，代表蛋白质的亚稳态构象。尽管有共同的三级折叠，丝氨酸或半胱氨酸蛋白酶的抑制，甲状腺激素的血液转运，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，肿瘤侵袭的调节，参与细胞分化和细胞凋亡的调节。这个项目的长期目标是了解亚稳态的折叠途径和亚稳态丝氨酸蛋白酶抑制剂折叠对正常和病理功能的影响，以及在赋予给定丝氨酸蛋白酶抑制剂的特定性质时，（抗凝血酶、α 1蛋白酶抑制剂和crmA），（ii）能够经历构象变化但没有抑制蛋白酶的能力（甲状腺素结合球蛋白）或（iii）既不起抑制剂的作用，也不发生丝氨酸蛋白酶抑制剂构象变化（血管紧张素）。目前的建议代表了一个协调重视一些最重要的悬而未决的问题，对serpin的结构和功能。该方案包括四个项目，解决这一目标的不同方面。研究包括关于丝氨酸和半胱氨酸蛋白酶的抑制机制的性质的结构以及丝氨酸蛋白酶抑制剂如何能够动力学地捕获与蛋白酶的复合物的研究（项目2，Steven Olson，P.I.），为什么非抑制性丝氨酸蛋白酶抑制剂血管紧张素原和甲状腺素结合球蛋白仍然需要丝氨酸蛋白酶抑制剂折叠（项目3，菲利普Patston，P.I.），以及丝氨酸蛋白酶抑制剂及其与蛋白酶和特异性配体的复合物的X射线结构（Project 4，Karl Volz，P.I.）。有三个核心组成的行政核心，分子生物学和细胞培养的核心，蛋白质表达和纯化的核心。所有三个核心将用于所有四个项目。该项目是跨部门和跨学院的合作，涉及芝加哥伊利诺伊大学四个部门和两个学院的调查人员以及一组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.