The structure and function of SGTA, a key regulator of protein quality control

蛋白质质量控​​制关键调节因子SGTA的结构和功能

• 批准号: BB/L006510/1
• 负责人: Stephen High
• 金额: $ 42.75万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL006510%2F1
• 关键词: structure; function; SGTA; key; regulator

Proteins are essential to life, providing important building blocks for our cells and performing numerous complex roles that maintain animal and human health and combat disease. Proteins are rather complex macromolecules, and this in turn means that making them is a complicated process made up of several stages, each of which can potentially go wrong resulting in the production of faulty or defective proteins. There are many reasons why faulty proteins might be made, including different kinds of physiological stress and mutations to the genes that encode them, but importantly the cell has developed a mechanism for checking its newly made proteins to make sure they are made correctly. This process is normally referred to as "protein quality control" and when it is operating correctly it acts to recognise and remove faulty proteins. This normal cellular quality control process is vitally important, since if faulty proteins are not dealt with quickly they have a tendency to stick to each other and clump together to form aggregates. In many cases these aggregates are toxic and can prevent cells from working properly, or even cause them to die. The misfolding and aggregation of proteins lies at the root of the prion diseases that are suffered by many animal species, including BSE and scrapie. Likewise, protein aggregates are a feature of human prion diseases, such as Creutzfeldt-Jakob disease, and neurological disorders, most notably Alzheimer's disease and Parkinson's disease. It is also suggested that one of the consequences of ageing is a reduced capacity for cellular protein quality control, and that this in turn might impact on ageing related diseases. Misfolded membrane proteins have a strong tendency to aggregate, and mammalian cells like ours seem to have developed a fast track system to recognise this class of proteins and deal with them quickly, thereby avoiding any potential problems they might cause. We have identified a protein called SGTA which acts as a quality control factor and plays a very important role in the cells ability to deal with mislocalised membrane proteins that are misfolded because they have ended up in the wrong location with a cell. There is also evidence that SGTA is linked to certain cancers and viral infections. However, although there is a strong case that SGTA is a critical component of cellular quality control pathways, we really know very little detail about how it works, and it is precisely this question that we will answer during the course of this project. In particular, we will find out how SGTA specifically recognises mislocalised membrane proteins, and establish what it does with these aberrant proteins once they are bound, focussing on its ability to inhibit their destruction and looking directly at its role in protein aggregation. The purpose of our research is to understand the normal workings of SGTA in a healthy cell that is capable of efficiently removing mislocalised membrane proteins and avoiding a build up of protein aggregates.

蛋白质对生命至关重要，为我们的细胞提供重要的构建模块，并发挥许多复杂的作用，维持动物和人类的健康并对抗疾病。蛋白质是相当复杂的大分子，这反过来意味着制造它们是一个由几个阶段组成的复杂过程，每个阶段都可能出错，导致产生错误或有缺陷的蛋白质。可能产生错误蛋白质的原因有很多，包括不同种类的生理压力和编码它们的基因突变，但重要的是细胞已经开发了一种检查新蛋白质的机制，以确保它们是正确的。这个过程通常被称为“蛋白质质量控制”，当它正确运行时，它会识别和去除有缺陷的蛋白质。这种正常的细胞质量控制过程是至关重要的，因为如果不迅速处理有缺陷的蛋白质，它们就有相互粘附并聚集在一起形成聚集体的趋势。在许多情况下，这些聚集体是有毒的，可以阻止细胞正常工作，甚至导致它们死亡。蛋白质的错误折叠和聚集是朊病毒疾病的根源，包括BSE和羊瘙痒病在内的许多动物物种都患有朊病毒疾病。类似地，蛋白质聚集体是人类朊病毒疾病（如克雅氏病）和神经系统疾病（最显著的是阿尔茨海默病和帕金森病）的特征。还表明，衰老的后果之一是细胞蛋白质质量控制能力降低，这反过来可能影响与衰老有关的疾病。 错误折叠的膜蛋白具有很强的聚集倾向，像我们这样的哺乳动物细胞似乎已经开发出一种快速跟踪系统来识别这类蛋白质并快速处理它们，从而避免它们可能引起的任何潜在问题。我们已经确定了一种称为SGTA的蛋白质，它作为一种质量控制因子，在细胞处理错误折叠的错误定位膜蛋白的能力中起着非常重要的作用，因为它们最终在细胞的错误位置。还有证据表明，SGTA与某些癌症和病毒感染有关。然而，尽管SGTA是细胞质量控制途径的关键组成部分，但我们对它如何工作的细节知之甚少，这正是我们将在本项目过程中回答的问题。特别是，我们将发现SGTA如何特异性识别错误定位的膜蛋白，并确定一旦它们被结合，它对这些异常蛋白的作用，重点是它抑制它们破坏的能力，并直接观察它在蛋白质聚集中的作用。我们研究的目的是了解SGTA在健康细胞中的正常工作，能够有效地去除错误定位的膜蛋白并避免蛋白质聚集体的积聚。

项目成果

Binding of SGTA to Rpn13 selectively modulates protein quality control.

SGTA与RPN13的结合选择性调节蛋白质质量控​​制。

• DOI: 10.1242/jcs.165209
• 发表时间: 2015-09-01
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Leznicki P;Korac-Prlic J;Kliza K;Husnjak K;Nyathi Y;Dikic I;High S
• 通讯作者: High S

Structural and functional insights into the E3 ligase, RNF126.

• DOI: 10.1038/srep26433
• 发表时间: 2016-05-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Krysztofinska EM;Martínez-Lumbreras S;Thapaliya A;Evans NJ;High S;Isaacson RL
• 通讯作者: Isaacson RL

Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control.

• DOI: 10.1186/s12915-018-0542-3
• 发表时间: 2018-07-11
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Martínez-Lumbreras S;Krysztofinska EM;Thapaliya A;Spilotros A;Matak-Vinkovic D;Salvadori E;Roboti P;Nyathi Y;Muench JH;Roessler MM;Svergun DI;High S;Isaacson RL
• 通讯作者: Isaacson RL

Solution structure of the SGTA dimerisation domain and investigation of its interactions with the ubiquitin-like domains of BAG6 and UBL4A.

• DOI: 10.1371/journal.pone.0113281
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Darby JF;Krysztofinska EM;Simpson PJ;Simon AC;Leznicki P;Sriskandarajah N;Bishop DS;Hale LR;Alfano C;Conte MR;Martínez-Lumbreras S;Thapaliya A;High S;Isaacson RL
• 通讯作者: Isaacson RL

SGTA interacts with the proteasomal ubiquitin receptor Rpn13 via a carboxylate clamp mechanism.

• DOI: 10.1038/srep36622
• 发表时间: 2016-11-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Thapaliya A;Nyathi Y;Martínez-Lumbreras S;Krysztofinska EM;Evans NJ;Terry IL;High S;Isaacson RL
• 通讯作者: Isaacson RL