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ANALYSIS OF ZDHHC17 INTERACTION NETWORKS AND PROTEIN INTERACTIONS LINKED TO NEURODEGENERATION

ZDHHC17 相互作用网络和与神经变性相关的蛋白质相互作用的分析

基本信息

批准号：
MR/R011842/1
负责人：
Luke Chamberlain
金额：
$ 51.7万
依托单位：
University of Strathclyde
依托单位国家：
英国
项目类别：
Research Grant
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=MR%2FR011842%2F1
关键词：
ANALYSIS ZDHHC17 INTERACTION NETWORKS PROTEIN

项目摘要

The cells in our body contain a diverse array of different proteins that coordinate and drive specific pathways, such as neuronal communication in the brain. These proteins are often tightly regulated to ensure that they perform their specific functions in the required spatial and temporal manner. A major way of regulating protein function is by specific chemical modifications that are made to the amino acid backbone, and a variety of different chemical groups are added to proteins that affect their activity. One important but poorly understood modification is "S-acylation", the attachment of fatty acids onto proteins. S-acylation of cellular proteins is catalysed by a family of twenty-four "zDHHC" enzymes. The importance of these enzymes for normal brain function is underscored by reported links between zDHHC enzyme dysfunction and conditions such as neurodegeneration, schizophrenia, and intellectual disability.Despite the importance of zDHHC enzymes, we lack fundamental knowledge about this protein family, including the substrate interaction networks of individual enzyme isoforms, how changes in these interactions contribute to disease pathology, and how these interactions can be targeted as a therapeutic strategy. Recent work from our group has provided an important breakthrough in this area by identifying a specific protein sequence that is recognised by the enzyme zDHHC17; this enzyme is essential for brain function and is associated with specific neurodegenerative disorders. In this project, we will exploit our new findings about the zDHHC17 recognition sequence to identify the substrate interaction network of this enzyme in neurons, providing a major advance in our understanding of the physiological functions of zDHHC17. In addition, we will investigate how the interaction of zDHHC17 with one of its key substrates, huntingtin, is affected in Huntington's disease to provide new insight into the pathogenesis of this neurodegenerative disorder. Finally, we will employ the novel information on the zDHHC17 recognition sequence to develop compounds that may have potential for the treatment of the neurodegenerative disease, neuronal ceroid lipofuscinosis. Collectively, these studies focused on the zDHHC17 recognition sequence will provide new information on the physiological functions of zDHHC17, its links with Huntington's disease, and the potential of this enzyme to serve as a novel therapeutic target for neuronal ceroid lipofuscinosis.

我们身体中的细胞含有各种不同的蛋白质，这些蛋白质协调和驱动特定的通路，例如大脑中的神经元通信。这些蛋白质通常受到严格调控，以确保它们以所需的空间和时间方式执行其特定功能。调节蛋白质功能的一种主要方法是对氨基酸骨架进行特定的化学修饰，并将各种不同的化学基团添加到蛋白质中以影响其活性。一种重要但知之甚少的修饰是“S-酰化”，即脂肪酸附着在蛋白质上。细胞蛋白质的S-酰化由二十四种“zDHHC”酶家族催化。这些酶对正常脑功能的重要性被zDHHC酶功能障碍与神经变性、精神分裂症和智力障碍等疾病之间的联系所强调。尽管zDHHC酶很重要，但我们缺乏关于这个蛋白质家族的基础知识，包括单个酶亚型的底物相互作用网络，这些相互作用的变化如何导致疾病病理学，以及如何将这些相互作用作为治疗策略。我们小组最近的工作在这一领域提供了一个重要的突破，确定了一种被酶zDHHC 17识别的特定蛋白质序列;这种酶对大脑功能至关重要，并与特定的神经退行性疾病有关。在这个项目中，我们将利用我们关于zDHHC 17识别序列的新发现来识别这种酶在神经元中的底物相互作用网络，为我们理解zDHHC 17的生理功能提供重大进展。此外，我们将研究如何相互作用的zDHHC 17与其关键底物之一，亨廷顿，是受影响的亨廷顿病，提供新的见解这种神经退行性疾病的发病机制。最后，我们将利用zDHHC 17识别序列的新信息来开发可能具有治疗神经退行性疾病神经元蜡样脂褐质沉积症潜力的化合物。总的来说，这些研究集中在zDHHC 17识别序列将提供新的信息zDHHC 17的生理功能，其与亨廷顿病的联系，这种酶作为一种新的治疗靶点神经元蜡样脂褐质沉积症的潜力。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of key features required for efficient S-acylation and plasma membrane targeting of sprouty-2.

DOI：
10.1242/jcs.249664
发表时间：
2020-11-05
期刊：
Journal of cell science
影响因子：
4
作者：
Locatelli C;Lemonidis K;Salaun C;Tomkinson NCO;Chamberlain LH
通讯作者：
Chamberlain LH

Regulatory effects of post-translational modifications on zDHHC S-acyltransferases.

DOI：
10.1074/jbc.rev120.014717
发表时间：
2020-10-23
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Zmuda F;Chamberlain LH
通讯作者：
Chamberlain LH

S-acylation of Sprouty and SPRED proteins by the S-acyltransferase zDHHC17 involves a novel mode of enzyme-substrate interaction.

DOI：
10.1016/j.jbc.2022.102754
发表时间：
2023-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Butler L;Locatelli C;Allagioti D;Lousa I;Lemonidis K;Tomkinson NCO;Salaun C;Chamberlain LH
通讯作者：
Chamberlain LH

LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein.

DOI：
10.1242/jcs.222257
发表时间：
2018-09-20
期刊：
Journal of cell science
影响因子：
4
作者：
Sutherland L;Ruhe M;Gattegno-Ho D;Mann K;Greaves J;Koscielniak M;Meek S;Lu Z;Waterfall M;Taylor R;Tsakiridis A;Brown H;Maciver SK;Joshi A;Clinton M;Chamberlain LH;Smith A;Burdon T
通讯作者：
Burdon T

Fam49/CYRI interacts with Rac1 and locally suppresses protrusions.

DOI：
10.1038/s41556-018-0198-9
发表时间：
2018-10
期刊：
Nature cell biology
影响因子：
21.3
作者：
Fort L;Batista JM;Thomason PA;Spence HJ;Whitelaw JA;Tweedy L;Greaves J;Martin KJ;Anderson KI;Brown P;Lilla S;Neilson MP;Tafelmeyer P;Zanivan S;Ismail S;Bryant DM;Tomkinson NCO;Chamberlain LH;Mastick GS;Insall RH;Machesky LM
通讯作者：
Machesky LM