How the proteasome works: resolving a critical new level of regulation

蛋白酶体如何工作：解决关键的新监管水平

• 批准号: BB/W016672/1
• 负责人: Paula Da Fonseca
• 金额: $ 68万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW016672%2F1
• 关键词: How; proteasome; works; resolving; critical

Proteasomes are essential cell regulators in all eukaryotes. They are involved in the turnover of most proteins by breaking down proteins that are old, damaged, or no longer needed. They also perform the highly regulated removal of specific proteins that signal to important and diverse events such as cell division, stress responses and chromatin maintenance. Despite 30 years of research, many of the fundamental aspects of proteasome function are still not fully characterised. We recently discovered an unexpected new level of proteasome regulation by divalent cations that challenges our current understanding of how the proteasome works. I want to build on our new data to unambiguously describe how proteasomes work inside the cells. For this I will use electron microscopy based structural analysis, together with biochemical and biophysical methods, to visualise in detail how they are regulated by divalent cations and how they recognise and process the proteins to be degraded. Because the proteasome is a critical cell regulator, understanding its fundamental working mechanisms will have a broad impact in biological sciences in general. The outputs of the proposed work have the potential of contributing to the clarification of critical mechanisms underlying conditions such as cancer progression, neurodegeneration, and aging, where proteasome dysfunction and calcium deregulation have been implicated, with impact for a wide range of beneficiaries. The proteasome is a well-established drug target for conditions including cancer, so in addition to improving basic knowledge the proposal has the potential to contribute to further developments in drug discovery and development.

蛋白酶体是所有真核生物必不可少的细胞调节剂。它们通过分解老化、受损或不再需要的蛋白质，参与大多数蛋白质的周转。它们还执行高度调控的特定蛋白质的去除，这些蛋白质是重要和多样化事件的信号，如细胞分裂，应激反应和染色质维持。尽管经过了30年的研究，蛋白酶体功能的许多基本方面仍然没有得到充分的描述。我们最近发现了二价阳离子对蛋白酶体调控的一个意想不到的新水平，这挑战了我们目前对蛋白酶体如何工作的理解。我想以我们的新数据为基础，明确地描述蛋白酶体是如何在细胞内工作的。为此，我将使用基于电子显微镜的结构分析，结合生物化学和生物物理方法，详细观察它们是如何被二价阳离子调节的，以及它们如何识别和处理要降解的蛋白质。由于蛋白酶体是一种关键的细胞调节剂，了解其基本工作机制将对生物科学产生广泛的影响。拟议工作的产出有可能有助于澄清癌症进展、神经退行性变和衰老等关键疾病的潜在机制，其中蛋白酶体功能障碍和钙调节失调已被涉及，并对广泛的受益者产生影响。蛋白酶体是一种成熟的药物靶点，可以治疗包括癌症在内的疾病，因此，除了提高基础知识外，该提议还可能有助于药物发现和开发的进一步发展。