Functional Diversity of J-protein Components of Hsp70 Chaperone Machinery

项目总结/摘要 蛋白质如何折叠，即获得其三维结构，是一个基本的生物学 这一过程对人类健康具有重要意义。错误折叠的蛋白质通常是有毒的， 由被称为“蛋白质折叠疾病”的神经变性疾病的数量来说明。 分子伴侣在重塑蛋白质结构中起着至关重要的作用--协助蛋白质从头合成 折叠、防止蛋白质聚集和分解蛋白质复合物。Hsp 70基 具有J蛋白作为专性组分的机器是最高度保守的机器之一， 分子伴侣系统。J蛋白是一组非常多样化的蛋白质，只有70个 共同的氨基酸J结构域。所有的J蛋白都具有刺激ATP酶活性的能力， 它们的伴侣Hsp 70，使它们能够捕获客户蛋白。但正是它们的功能多样性 使他们能够协调HSP 70的能力，参与各种复杂的， 多种生物功能。本建议的重点是了解的基础上的具体性， J蛋白功能。 酵母细胞质中的两个J蛋白被选择用于深入分析：Sis 1和Zuo 1。这 选择是基于它们的关键重要性和它们的高度序列保守性。他们的 人类同源物能够替代酵母蛋白，因此这项工作的结果将 作为理解其他生物中J蛋白功能的范例。了解 由于Sis 1的特异性，它在酵母朊病毒繁殖中的功能将被利用，事实上 是朊病毒复合物裂解所必需的。因此，结果也将产生重要的 关于这些自我复制的淀粉样蛋白的生物发生和繁殖的信息 集料. Zuo 1是一种高度保守的核糖体相关分子伴侣， Hsp 70在离开核糖体时与新生多肽结合。核糖体相关分子伴侣 作为蛋白质合成和蛋白质折叠之间的联系，因此是细胞的关键。 生产功能性蛋白质。此外，我们将研究分子伴侣在 细胞核，专注于新的独立于分子伴侣的调节功能 活动

Project Summary/Abstract How proteins fold, that is attain their three-dimensional structure, is a fundamental biological process with important implications for human health. Misfolded proteins are often toxic, as illustrated by the number of neurodegenerative diseases referred to as "protein folding diseases". Molecular chaperones play vital roles in remodeling protein structure -- assisting de novo protein folding, preventing protein aggregation and disassembling protein complexes. Hsp70-based machineries, having J-proteins as obligate components, are amongst the most highly conserved molecular chaperone systems. J-proteins are a very diverse set of proteins, having only the 70 amino acid J-domain in common. All J-proteins share the ability to stimulate the ATPase activity of their partner Hsp70s, allowing them to capture client proteins. But it is their functional diversity that enables them to orchestrate Hsp70¿s capacity to participate in a wide array of complex and diverse biological functions. This proposal focuses on understanding the basis of the specificity of J-proteins function. Two J-proteins of the yeast cytosol have been chosen for in depth analysis: Sis1 and Zuo1. This choice is based on their critical importance and their high degree of sequence conservation. Their human homologs are able to substitute for the yeast proteins, thus the outcome of this work will serve as a paradigm for understanding J-protein function in other organisms. To understand the specificity of Sis1, its function in the propagation of yeast prions will be exploited, as it is specifically required for fragmentation of prion complexes. Thus, results will also yield important information about the biogenesis and propagation of these self-replicating amyloid protein aggregates. Zuo1 is a highly conserved ribosome-associated chaperone that facilitates interaction of Hsp70 with nascent polypeptides as they exit the ribosome. Ribosome-associated chaperones serve as a link between protein synthesis and protein folding and are thus a key to the cell¿s production of functional proteins. In addition, we will investigate roles of molecular chaperones in the nucleus, focusing on novel regulatory functions independent of and separable from chaperone activity.