Proteostasis at cellular membranes

项目摘要 细胞膜不仅将细胞内过程区室化，而且还作为细胞内过程的动力中心。 许多多蛋白信号复合物、癌蛋白和肿瘤抑制物的组装。因此 大多数目前的治疗剂（>60%）靶向占人类细胞膜蛋白的约23%的膜蛋白。 蛋白质组在对环境线索和药物的反应中，细胞的蛋白质补体 改变膜以建立校准的响应，如果受到干扰，则影响疾病状态，例如， 癌症、心脏和神经系统疾病。泛素-蛋白酶体系统（UPS）非常适合这项任务， 以无与伦比的精确度转换调节蛋白。到目前为止，我们对分子细节的理解 膜蛋白周转是如何通过UPS介导的蛋白水解调节仍然粗略。 我们正在进行新的UPS调节蛋白质降解的机制研究 在我们以前的工作与FBXL 2，一个高度保守的F盒蛋白建模膜途径 含有典型的C-末端CaaX异戊烯基序，用于定位于细胞膜。的完整性 CaaX基序是FBXL 2组装成活性SCF泛素连接酶复合物并相互作用所必需 在细胞膜上有两种底物，p85β和IP 3R 3。有趣的是，我们最近发现了GGtase 3， 新的哺乳动物异戊烯基转移酶，并确定FBXL 2-泛素连接酶为 通过GGT酶3的异戊烯化。该提案采用跨学科方法来研究监管， UPS在哺乳动物细胞存活中的膜锚定蛋白周转的生物学相关性， 增殖和GGtase 3生物学的完整表征。

Project Summary Cellular membranes not only compartmentalize intracellular processes but also serve as the dynamic hubs for the assembly of many multi-protein signaling complexes, oncoproteins, and tumor suppressors. Accordingly, a majority of current therapeutics (>60%) target membrane proteins that make up approximately 23% of human proteome. In response to environmental cues and pharmacological drugs, the protein complement of cellular membranes is altered to mount a calibrated response, which, if perturbed, impacts the disease state, e.g., cancer, cardiac and neurological disorders. The ubiquitin-proteasome system (UPS) aptly fits the task to swiftly turnover the regulatory proteins with unmatched precision. To date, our understanding of the molecular details of how membrane protein turnover is regulated by UPS-mediated proteolysis remain sketchy. We are conducting the mechanistic studies in the investigations of novel UPS-regulated protein degradation pathways at membranes modeled on our previous work with FBXL2, a highly conserved F-box protein containing a typical C-terminal CaaX prenylation motif for localization to cellular membranes. The integrity of the CaaX motif is necessary for FBXL2 to assemble into an active SCF ubiquitin ligase complex and interact with two substrates, p85β and IP3R3, at cellular membranes. Interestingly, we recently discovered GGtase3, a new mammalian prenyltransferase and identified FBXL2-ubiquitin ligase as the physiological target for prenylation by GGTase3. This proposal uses an interdisciplinary approach to investigate the regulation and biological relevance of membrane anchored protein turnover by UPS in mammalian cell survival and proliferation, and full characterization of GGtase3 biology.