The Mammalian Arg/N-End Rule Pathway: Substrates, Functions, and Mechanisms

描述（由申请人提供）：泛素-蛋白酶体系统（泛素系统）调节的蛋白质水解在许多生物过程中起重要作用，并对人类健康产生重大影响。我们在过去三十年中对泛素系统和n端规则通路的研究在很大程度上是由目前的资助（DK039520）实现的，目前已是第27年的支持。这个更新应用是关于蛋白质降解的n端规则途径。在真核生物中，这一途径是泛素系统的一个特定部分。n端规则将蛋白质的体内半衰期与其末端残基的身份联系起来。蛋白质降解的n端规则途径包括两个不同的分支，Ac/ n端规则途径和Arg/ n端规则途径。Ac/ n端规则通路是我们实验室在2010年发现的。它能识别n端乙酰化残基的蛋白质。Arg/ n端规则通路是我们实验室在1986年发现的，它针对特定的未乙酰化的n端残基。这条途径仍然是生物学见解的源泉，也是我们研究的主要焦点。本次（DK039520）更新申请是关于Arg/N-end规则通路和新的生理Arg/ n -规则底物的鉴定（和详细研究）。因此，DK039520之前的拨款标题（“泛素连接酶、N-End规则通路的机制和功能”）在本次续期申请中修改如下，以反映其当前的重点：“哺乳动物Arg/N-End规则通路：底物、功能和机制”。这项更新申请的项目包括哺乳动物（小鼠）Arg/N-end规则通路的特定生理底物的功能和机制研究，以及新的哺乳动物Arg/N-end规则底物的鉴定，包括那些作为促凋亡蛋白片段的底物，即在细胞凋亡（一种特定的程序性细胞死亡）过程中形成的片段，增加了细胞凋亡的可能性。

DESCRIPTION (provided by applicant): Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes, and has major ramifications for human health. Our studies of the ubiquitin system and the N-end rule pathway over the last three decades were made possible, to a large extent, by the present grant (DK039520), currently in its 27th year of support. This renewal application is about the N-end rule pathway of protein degradation. In eukaryotes, this pathway is a specific part of the ubiquitin system. The N-end rule relates the in vivo half-life of a protein to the identity of its -terminal residue. The N-end rule pathway of protein degradation consists of two distinct branches, the Ac/N-end rule pathway and the Arg/N-end rule pathway. The Ac/N-end rule pathway was discovered by our laboratory in 2010. It recognizes proteins with N-terminally acetylated residues. The Arg/N-end rule pathway, which targets specific unacetylated N-terminal residues, was discovered by our laboratory in 1986. This pathway continues to be a fount of biological insights and remains a major focus of our studies. The present (DK039520) renewal application is about the Arg/N-end rule pathway and the identification (as well as detailed studies) of new physiological Arg/N-rule substrates. Therefore the previous title of the DK039520 grant ("Ubiquitin Ligases, Mechanisms and Functions of the N-End Rule Pathway") was modified as follows in the present renewal application, to reflect its current emphasis: "The Mammalian Arg/N-End Rule Pathway: Substrates, Functions, and Mechanisms". The projects of this renewal application include functional and mechanistic studies of specific physiological substrates of the mammalian (mouse) Arg/N-end rule pathway, and the identification of new mammalian Arg/N-end rule substrates, including those that act as proapoptotic protein fragments, i.e., fragments whose formation during apoptosis (a specific kind of programmed cell death) increases the probability of apoptosis.