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

描述(由申请人提供)：由泛素-蛋白酶体系统(泛素系统)调节的蛋白分解在许多生物学过程中起着重要作用，并对人类健康具有重大影响。我们在过去30年中对泛素系统和N末端规则途径的研究在很大程度上是由于目前的赠款(DK039520)，目前处于其第27个资助年头。这一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殊部分。N-端规则将蛋白质在体内的半衰期与其末端残基的同一性联系起来。蛋白质降解的N-端调控通路由Ac/N-end调控通路和Arg/N-end调控通路两个不同的分支组成。Ac/N末端规则通路是本实验室在2010年发现的。它识别N-末端乙酰化残基的蛋白质。本实验室于1986年发现了针对特定非乙酰化N-末端残基的Arg/N-end规则通路。这条途径仍然是生物学洞察力的源泉，也是我们研究的主要焦点。目前(DK039520)的更新应用是关于Arg/N-end规则途径和新的生理Arg/N-规则底物的鉴定(以及详细研究)。因此，DK039520基金以前的标题(“泛素连接、N-端规则途径的机制和功能”)在本更新申请中修改如下，以反映其当前的重点：“哺乳动物Arg/N-端规则途径：底物、功能和机制”。这一更新应用的项目包括对哺乳动物(小鼠)Arg/N-end规则通路的特定生理底物的功能和机制的研究，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.