Desiphering the structural origins of functional multimodality in bacterial mechanosensitive ion channels

解析细菌机械敏感离子通道功能多模态的结构起源

基本信息

批准号：
BB/S018069/1
负责人：
Christos Pliotas
金额：
$ 59.78万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS018069%2F1
关键词：
Desiphering structural origins functional multimodality

项目摘要

Ion channels are central to life sciences due to direct involvement in signal transduction, aging, cancer and neurodegeneration. Despite progress in the fundamental understanding of the structure and function of specific membrane proteins (Nobel Prizes in Chemistry 1988, 1997, 2003 and 2012), this has only been the tip of the iceberg. There is now an immediate need for the development of novel triggers to control pores in the cell membrane of deadly pathogens and tackle antimicrobial resistance, the most common cause of death worldwide. We anticipate to achieve that by exploiting an ancient and ubiquitous mechanism of ion channel regulation named mechanosensation. The latter is the ability of membrane proteins to sense tension changes occurring within the lipid membrane and respond to these by altering their structure and function. This proposal aims to gain a fundamental understanding of mechanosensation and decipher the molecular basis of its co-existence with other forms of ion channel regulation. To this end, we will dissect the individual steps that form its molecular basis and identify the common, but essential structural elements responsible to transduce pressure-sensing abilities to channels. The fundamental aspect of the underlying impact of the lipid membrane in ion channel regulation along with the physiological role of the functional versatility of pressure sensitive channels will be elucidated. To this end, we will identify the unique structural features which allow functional multimodality of mechanosensitive channels and their ability to respond to other stimuli, such as ions, pH or specific molecules, in addition to mechanical triggers. Within the project we will develop and follow an integrated multidisciplinary approach in order to establish a link between mechanical-activation and ligand-gating. The proposed studies will involve using a suite of state-of-the-art structural (Cryo Electron Microscopy and X -Ray crystallography), biochemical (Protein Purification), biophysical (Electron Paramagnetic Resonance spectroscopy and Electrophysiology) and sophisticated computational methods (Molecular Dynamics) to address questions pertaining to the mechanism and regulation of distinct members of the bacterial mechanosensitive ion channel family at a molecular level.Collectively, we anticipate to translate forces within the membrane participating in the mechanical activation of channels into specific molecular stimuli, which would mimic mechanotransduction. Similar to optogenetics, a field which has massively evolved over the last years and is based on the interaction of proteins with the ancient physical property of light, pressure sensing, one of nature's most fundamental regulatory mechanisms, would enable a radically novel field to emerge.

由于直接参与信号转导，衰老，癌症和神经变性，离子通道是生命科学的核心。尽管在对特定膜蛋白的结构和功能的基本理解方面取得了进步（诺贝尔化学奖学金1988，1997，2003和2012），但这只是冰山一角。现在，新型触发因素即时需要在致命病原体的细胞膜中控制毛孔，并应对抗菌耐药性，这是全世界最常见的死亡原因。我们预计通过利用称为机械敏化的离子通道调节的古老且普遍存在的机制来实现这一目标。后者是膜蛋白感知脂质膜内发生的张力变化的能力，并通过改变其结构和功能来响应这些变化。该建议旨在获得对机械敏化的基本理解，并破译其与其他形式的离子通道调节共存的分子基础。为此，我们将剖析形成其分子基础的各个步骤，并确定负责将压力密度感应能力转化为通道的共同但必不可少的结构元素。将阐明脂质膜在离子通道调节中的潜在影响以及压力敏感通道功能多功能性的生理作用的基本方面。为此，我们将确定机械敏感通道的功能多模态及其对其他刺激的响应能力，例如离子，pH或特定分子，除了机械触发器之外，还可以识别出唯一的结构特征。在项目中，我们将开发并遵循一种综合的多学科方法，以建立机械激活和配体门控之间的联系。拟议的研究将涉及使用一套最先进的结构（冷冻电子显微镜和X射线晶体学），生化（蛋白质纯化），生物物理（电子顺式共振光谱和电生理学和电生理学）和复杂的计算方法（分子动力学）的机制和定义机制的机制构成机制的调节，以构成与机制的定义机制，以构成差异的机制，并收缩的是，我们预计将在膜内翻译力，将通道的机械激活参与特定的分子刺激，这将模拟模仿机械转移。类似于光遗传学，该领域在过去几年中已经大规模发展，并且基于蛋白质与光，压力传感的古老物理特性的相互作用，这是自然界最基本的调节机制之一，它将使一个根本新颖的领域出现。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tension mediated mechanical activation and pocket delipidation lead to an analogous MscL state

张力介导的机械激活和口袋脱脂导致类似的 MscL 状态

DOI：
10.1101/2021.04.01.438050
发表时间：
2021
期刊：
影响因子：
0
作者：
Wang B
通讯作者：
Wang B

Genetic and cellular characterization of MscS-like putative channels in the filamentous fungus Aspergillus nidulans.

DOI：
10.1080/19336950.2022.2098661
发表时间：
2022-12
期刊：
CHANNELS
影响因子：
3.3
作者：
Dionysopoulou, Mariangela;Yan, Nana;Wang, Bolin;Pliotas, Christos;Diallinas, George
通讯作者：
Diallinas, George

Membrane force reception: mechanosensation in G protein-coupled receptors and tools to address it

DOI：
10.1016/j.cophys.2023.100689
发表时间：
2023-07-06
期刊：
CURRENT OPINION IN PHYSIOLOGY
影响因子：
2.5
作者：
Hardman，Katie;Goldman，Adrian;Pliotas，Christos
通讯作者：
Pliotas，Christos

Darobactin B Stabilises a Lateral-Closed Conformation of the BAM Complex in E. coli Cells

Darobactin B 稳定大肠杆菌细胞中 BAM 复合物的横向闭合构象

DOI：
10.1002/ange.202218783
发表时间：
2023
期刊：
Angewandte Chemie
影响因子：
0
作者：
Haysom S
通讯作者：
Haysom S

HDX-guided EPR spectroscopy to interrogate membrane protein dynamics.

DOI：
10.1016/j.xpro.2022.101562
发表时间：
2022-09-16
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Lane, Benjamin J.;Wang, Bolin;Ma, Yue;Calabrese, Antonio N.;El Mkami, Hassane;Pliotas, Christos
通讯作者：
Pliotas, Christos

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Christos Pliotas其他文献

Activation and Complex Regulation of the Kef Potassium Efflux System During Protection of Bacteria Against Toxic Electrophiles

DOI：
10.1016/j.bpj.2010.12.763
发表时间：
2011-02-02
期刊：
Conference abstract
影响因子：
作者：
Tim Rasmussen;Christos Pliotas;Lisbeth Lyngberg;Jess Healy;Wendy Bartlett;Samantha Miller;Tarmo P. Roosild;Samantha Castronovo;Stuart J. Conway;Ian R. Booth
通讯作者：
Ian R. Booth