RUI: Dual regulated control over the catalytic and membrane binding activity of acyl protein thioesterases
RUI:对酰基蛋白硫酯酶的催化和膜结合活性的双重调节控制
基本信息
- 批准号:1812971
- 负责人:
- 金额:$ 25.03万
- 依托单位:
- 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:2018-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Palmitoylation is the reversible attachment of long lipid chains to proteins. It controls essential biological functions including cell signaling, immune regulation, and ion transport. Detachment of these lipid chains and recycling of membrane bound proteins is performed by acyl protein thioesterases (APTs), a conserved class of enzymes linked with cancer progression, neural degeneration, and bacterial pathogenicity. This research project will investigate the biological regulation of APTs, focusing on the role of protein flexibility and dynamics in controlling APT activity. The complex regulation of APT activity presents an intricate system for understanding how protein dynamics can regulate protein function. The dynamic regulation of APTs also has applications in understanding essential signaling pathways and disease states across human and bacterial systems. The research will also provide training opportunities for multiple undergraduate students within the investigator's laboratory and for broader investigations within linked classroom undergraduate laboratories. For classroom applications, an inquiry-based molecular biophysics laboratory will be added to the biochemistry major at Butler University and will be assessed for its effect on student learning and STEM career outcomes. This course and its outcomes will also be integrated with a previous NSF funded inquiry-based laboratory in biochemistry studying protein structure and function. To reach the broader community, a molecular biophysics symposium will be held at local undergraduate research conference and hands-on demonstrations of basic protein structure will be presented to young scientists at a public event aimed at exciting K-12 students about scientific discovery. APTs catalyze the depalmitoylation of S-acylated proteins attached to the plasma membrane. An APT homologue from a gram-negative pathogen exists in conformational equilibrium between a closed and open state that is hypothesized to regulate its biological activity. Interconversion between these closed and open states is dependent on the structural dynamics of a flexible loop overlapping the active site. The structural properties of this flexible loop provide a straightforward model for how the enzymatic activity of APTs could be regulated and localized at the plasma membrane. The goal of this project is to understand the interplay between the protein loop dynamics and regulation of the catalytic and membrane binding activity of human and bacterial APTs. The central hypothesis is that structural rearrangement of this flexible, hydrophobic loop dually controls the catalytic and membrane binding activity of APTs. To address this hypothesis, a series of studies will be conducted to understand the loop dynamics, structural transition, and biological importance of hypothesized structural rearrangements within human and bacterial APTs. Confirmation of the dynamic nature of this flexible loop and its dual roles will provide a novel model for controlling the biological function of APTs.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.
棕榈酰化是长脂链与蛋白质的可逆连接。它控制着基本的生物学功能,包括细胞信号传导、免疫调节和离子转运。这些脂质链的分离和膜结合蛋白的再循环由酰基蛋白硫酯酶(APT)进行,所述酰基蛋白硫酯酶是与癌症进展、神经变性和细菌致病性相关的一类保守酶。本研究项目将研究APT的生物调节,重点是蛋白质的灵活性和动力学在控制APT活性中的作用。APT活性的复杂调节为理解蛋白质动力学如何调节蛋白质功能提供了一个复杂的系统。APTs的动态调节也可用于理解人类和细菌系统中的基本信号通路和疾病状态。该研究还将为研究者实验室内的多名本科生提供培训机会,并在链接的课堂本科生实验室内进行更广泛的调查。对于课堂应用,一个基于探究的分子生物物理实验室将被添加到巴特勒大学的生物化学专业,并将评估其对学生学习和STEM职业成果的影响。本课程及其成果也将与以前的NSF资助的生物化学研究蛋白质结构和功能的调查为基础的实验室整合。为了接触更广泛的社区,将在当地本科生研究会议上举行分子生物物理学研讨会,并在旨在激发K-12学生对科学发现的公开活动中向年轻科学家展示基本蛋白质结构的实践演示。 APT催化附着于质膜的S-酰化蛋白质的脱棕榈酰化。来自革兰氏阴性病原体的APT同源物存在于封闭和开放状态之间的构象平衡中,假设其调节其生物活性。这些封闭和开放状态之间的相互转换依赖于与活性位点重叠的柔性环的结构动力学。这种灵活的环的结构特性提供了一个简单的模型,可以调节和定位在质膜上的酶活性的APT。该项目的目标是了解蛋白质环动力学与人类和细菌APT的催化和膜结合活性调节之间的相互作用。中心假设是,这种灵活的,疏水环的结构重排双重控制APTs的催化和膜结合活性。为了解决这一假设,将进行一系列的研究,以了解循环动力学,结构转换,以及在人类和细菌APT假设的结构重排的生物学重要性。这个灵活的循环和它的双重角色的动态性质的确认将提供一个新的模型,用于控制APTs的生物功能。这个奖项反映了NSF的法定使命,并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。
项目成果
期刊论文数量(0)
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Randal Johnson其他文献
Measuring Outcomes in Orthopaedics: Implementation of an Outcomes Program in an Outpatient Orthopaedic Practice
衡量骨科成果:在门诊骨科实践中实施成果计划
- DOI:
10.1097/nor.0000000000000103 - 发表时间:
2014 - 期刊:
- 影响因子:0.7
- 作者:
M. Rodts;R. Glanzman;Adam L Gray;Randal Johnson;Dennis Viellieu;F. Hachem - 通讯作者:
F. Hachem
Randal Johnson的其他文献
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{{ truncateString('Randal Johnson', 18)}}的其他基金
An Integrated Series of Student-driven, Research-based Undergraduate Laboratory Courses Linking Chemical Biology, Biochemistry, and Neurobiology
一系列以学生为主导、以研究为基础的本科实验室课程,将化学生物学、生物化学和神经生物学联系起来
- 批准号:
1140526 - 财政年份:2012
- 资助金额:
$ 25.03万 - 项目类别:
Standard Grant
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