Regulation of protein degradation and homeostasis by ubiquitylation

通过泛素化调节蛋白质降解和稳态

• 批准号: MC_UU_00018/3
• 负责人: Yogesh Kulathu
• 金额: $ 397.68万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00018%2F3
• 关键词: Regulation; protein; degradation; homeostasis; ubiquitylation

The majority of cellular functions are performed by proteins, making it vital to a cell to maintain functional proteins and destroy damaged ones, a process known as proteostasis. There is a progressive decline in proteostasis during the ageing process that results in the accumulation of damaged proteins. Loss of proteostasis and accumulation of misfolded and aggregated proteins is a common contributing factor to age-related diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS). Damaged proteins need to be tagged with a destruction signal called ubiquitin. The ubiquitin signals are recognized by the proteasome, a large molecular machine which unfolds and degrades the damaged proteins. Ubiquitin signals are removed by a family of enzymes called deubuiquitinating enzymes (DUBs) and in line with this important regulatory function, mutated DUBs are implicated in several human diseases. The main goals of our research are to understand how ubiquitin signals target proteins for degradation, and how protein degradation is regulated by DUBs. I anticipate that our research will provide important insights into how proteostasis is regulated. An improved understanding of this fundamental process will form the basis for the development of novel strategies to combat neurodegenerative disorders

细胞的大部分功能是由蛋白质完成的，这使得维持功能蛋白质和破坏受损蛋白质对细胞至关重要，这一过程被称为蛋白质稳定。在衰老过程中，蛋白质稳定性逐渐下降，导致受损蛋白质的积累。蛋白平衡的丧失以及错误折叠和聚集的蛋白质的积累是阿尔茨海默病、亨廷顿病、帕金森病和肌萎缩侧索硬化症(ALS)等与年龄相关的疾病的常见因素。受损的蛋白质需要标记一种称为泛素的破坏信号。泛素信号由蛋白酶体识别，蛋白酶体是一台大分子机器，负责展开和降解受损的蛋白质。泛素信号被称为脱辅酶(DUBS)的一系列酶去除，根据这一重要的调节功能，突变的DUBS与几种人类疾病有关。我们研究的主要目标是了解泛素是如何向蛋白质发出降解信号的，以及蛋白质降解是如何由DUBS调控的。我预计，我们的研究将为蛋白质调控提供重要的见解。对这一基本过程的更好理解将为开发抗击神经退行性疾病的新策略奠定基础

项目成果

Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2.

• DOI: 10.1016/j.molcel.2021.08.024
• 发表时间: 2021-10-21
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Abdul Rehman SA;Armstrong LA;Lange SM;Kristariyanto YA;Gräwert TW;Knebel A;Svergun DI;Kulathu Y
• 通讯作者: Kulathu Y

Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability.

• DOI: 10.1016/j.molcel.2018.02.023
• 发表时间: 2018-04-05
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Kwasna D;Abdul Rehman SA;Natarajan J;Matthews S;Madden R;De Cesare V;Weidlich S;Virdee S;Ahel I;Gibbs-Seymour I;Kulathu Y
• 通讯作者: Kulathu Y

Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies.

• DOI: 10.1371/journal.pone.0253364
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Armstrong LA;Lange SM;Dee Cesare V;Matthews SP;Nirujogi RS;Cole I;Hope A;Cunningham F;Toth R;Mukherjee R;Bojkova D;Gruber F;Gray D;Wyatt PG;Cinatl J;Dikic I;Davies P;Kulathu Y
• 通讯作者: Kulathu Y

Characterization of protease activity of Nsp3 from SARS-CoV-2 and its in vitro inhibition by nanobodies

SARS-CoV-2 Nsp3 蛋白酶活性的表征及其纳米抗体的体外抑制

• DOI: 10.1101/2020.12.09.417741
• 发表时间: 2020
• 作者: Armstrong L

Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach.

B 细胞激活的合成生物学：使用重建方法了解 B 细胞抗原受体的信号放大。

• DOI: 10.1515/hsz-2018-0308
• 发表时间: 2019
• 期刊: Biological chemistry
• 影响因子: 3.7
• 作者: Kulathu Y