Structure and Function of a novel and pervasive Ubiqitin-binding module

描述(申请人提供)：我们了解泛素如何控制各种过程的方法之一是定义能够非共价结合泛素的蛋白质相互作用模块。在已经涉及泛素依赖过程的蛋白质中找到这样的模块，可以发现这些蛋白质在分子水平上如何发挥作用的新方面。此外，在其他蛋白质中发现这样的模块可能意味着泛素在之前没有被怀疑的过程中扮演了一个角色。我们发现WD40 Beta螺旋桨的一个子集可以非共价结合Ub。这导致我们假设许多WD40β推进器可能结合泛素，从而为各种生物过程提供新的泛素依赖控制。这项提议将着手发现结合Ub的新的Beta-螺旋桨，并发现这种相互作用的结构基础。 公共卫生相关性这项提案寻求关于泛素如何控制各种细胞过程的新知识。这项工作的中心是发现泛素是如何非共价结合到WD40贝塔推进器上的，WD40贝塔推进器存在于许多具有不同功能的蛋白质中。WD40β螺旋桨蛋白涉及新陈代谢、糖尿病、炎症、免疫学、衰老和神经生物学等方面。这项工作保证了对泛素如何调控正常和致病过程的机械性洞察，这是许多NIH研究所特别感兴趣的。

DESCRIPTION (provided by applicant): One of the ways we can understand how ubiquitin controls various processes is to define the protein interaction modules that can non-covalently bind ubiquitin. Finding such modules within proteins that are already implicated in ubiquitin-dependent processes can uncover new aspects for how these proteins function at the molecular level. Furthermore, finding such modules in other proteins can implicate a role for ubiquitin in processes where it was previously not suspected. We have found that a subset of WD40 beta propellers can bind Ub non covalently. This has led us to hypothesize that many WD40 beta propellers might bind ubiquitin and thus provide new dimension of ubiquitin-dependent control to a variety of biological processes. This proposal will set out to discovery new beta-propellers that bind Ub and discover the structural basis for this interaction. PUBLIC HEALTH RELEVANCE This proposal seeks new knowledge on how ubiquitin might control a wide variety of cellular processes. The work centers on discovering how ubiquitin non- covalently binds to WD40 beta propellers, which are found in many proteins with diverse functions. WD40 beta propeller proteins are involved in aspects of metabolism, diabetes, inflammation, immunology, aging, and neurobiology. This work promises mechanistic insight into how ubiquitin might regulate normal and pathogenic processes, which are of particular interest to many NIH institutes.