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Mechanism and Dynamics of the YidC Insertase in Membrane Protein Insertion

YidC 插入酶在膜蛋白插入中的机制和动力学

基本信息

批准号：
1814936
负责人：
Ross Dalbey
金额：
$ 70万
依托单位：
Ohio State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1814936&HistoricalAwards=false
关键词：
Mechanism Dynamics YidC Insertase Membrane

项目摘要

This project examines how the bio-machine named YidC inserts and folds proteins into the membrane bilayer. Protein insertion into membranes is one of the most critical processes in biology, and understanding the mechanisms by which proteins are transported across or integrated into membranes has enormous potential impact for understanding cellular and organismal structure, function and health. The project will yield, as yet undiscovered, fundamental information on the function of YidC, which is key to understanding how biological membranes are assembled, maintain their identity, and support many functions such as signaling and transport. The resulting new knowledge on biogenesis of membrane proteins could also impact human health-related research in the future since membrane proteins make up more than 50% of the known drug targets. The project will also provide opportunities for training students in a multidisciplinary research environment involving molecular biology, biochemical and biophysical approaches. The goal of the research is to determine how YidC functions to insert proteins into the cell membrane. YidC is novel as a membrane insertase as it contains a hydrophilic cavity that is crucial for its insertase and chaperone function. YidC can function on its own or cooperate with the Sec machinery to insert proteins. The project utilizes fluorescence spectroscopy, electron paramagnetic resonance spin labeling, and single molecule approaches to examine the dynamics and structural relationships of membrane insertion events. The research specifically aims to determine the mechanism of action and dynamics of YidC in membrane protein insertion, elucidate the interactions in the YidC/Sec machinery complex, and identify features of membrane protein substrates that determine selection of YidC and Sec translocase pathways in E. coli. The project will advance the field of membrane protein insertion in bacteria and will impact understanding of similar pathways in human cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目研究了名为YidC的生物机器如何将蛋白质插入和折叠到膜双分子层中。蛋白质插入膜是生物学中最关键的过程之一，了解蛋白质跨膜运输或整合到膜中的机制对理解细胞和生物体的结构、功能和健康具有巨大的潜在影响。该项目将产生迄今尚未发现的关于YidC功能的基本信息，这是理解生物膜如何组装、保持其特性以及支持诸如信号传导和运输等许多功能的关键。由此产生的关于膜蛋白生物发生的新知识也可能影响未来与人类健康相关的研究，因为膜蛋白占已知药物靶点的50%以上。该项目还将为学生提供在涉及分子生物学、生物化学和生物物理学方法的多学科研究环境中进行培训的机会。这项研究的目的是确定YidC如何将蛋白质插入细胞膜。YidC是一种新颖的膜插入酶，因为它含有一个亲水空腔，这对其插入酶和伴侣蛋白的功能至关重要。YidC可以单独发挥作用，也可以与Sec机制合作插入蛋白质。该项目利用荧光光谱、电子顺磁共振自旋标记和单分子方法来研究膜插入事件的动力学和结构关系。本研究旨在确定YidC在膜蛋白插入中的作用机制和动力学，阐明YidC/Sec机制复合体中的相互作用，并确定膜蛋白底物在大肠杆菌中决定YidC和Sec转位酶途径选择的特征。该项目将推动细菌膜蛋白插入领域的发展，并将影响对人类细胞中类似途径的理解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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）

Tracking the Stepwise Movement of a Membrane-inserting Protein In Vivo

DOI：
10.1016/j.jmb.2019.10.010
发表时间：
2020-01-17
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
He, Haoze;Kuhn, Andreas;Dalbey, Ross E.
通讯作者：
Dalbey, Ross E.

Polarity/charge as a determinant of translocase requirements for membrane protein insertion

DOI：
10.1016/j.bbamem.2020.183502
发表时间：
2021-02-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
影响因子：
3.4
作者：
Hariharan, Balasubramani;Pross, Eva;Dalbey, Ross E.
通讯作者：
Dalbey, Ross E.

A hydrophilic microenvironment in the substrate-translocating groove of the YidC membrane insertase is essential for enzyme function.

DOI：
10.1016/j.jbc.2022.101690
发表时间：
2022-03
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Chen Y;Sotomayor M;Capponi S;Hariharan B;Sahu ID;Haase M;Lorigan GA;Kuhn A;White SH;Dalbey RE
通讯作者：
Dalbey RE

YidC as a potential antibiotic target