Examination and Reconstruction of Alternate Allosteric Networks in Engineered LacI/GalR Transcription Factors

工程 LacI/GalR 转录因子中替代变构网络的检查和重建

基本信息

批准号：
1921061
负责人：
Corey Wilson
金额：
$ 65.21万
依托单位：
Georgia Tech Research Corporation
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1921061&HistoricalAwards=false
关键词：
Examination Reconstruction Alternate Allosteric Networks

项目摘要

This project aims to understand and predict how proteins (i.e., transcription factors) that turn genes on-and-off develop the means to process information and interact with nearby surroundings. The mechanism in which proteins process signal information is called allosteric communication. While the study of allosteric communication has been underway for more than four decades, critical details of these fundamental processes are still poorly understood. This gap in knowledge prevents scientists and engineers from designing new proteins with custom-built communication abilities. Accordingly, the focus of the current project is to elucidate the rules that will enable scientists to build allosteric communication in a family of transcription factors that process a broad range of signals. This research will expand the scientific communities understanding of allosteric communication and enable the development of new tools that can be used to benefit society (e.g., new and less expensive process controls for bio-industrial applications, and systems for use in personalized medicine). Moreover, this project will involve the training and education of the next generation of scientists, specifically Ph.D. level graduate students. Protein allostery is a vitally important protein function that has proven to be a vexing problem to understand at the molecular level. Allosteric communication is a hallmark of many transcription factors used to control gene expression and have enabled synthetic biologist to reprogram cells. The specific goal of this research is to leverage the basic structure and function relationship of the lactose repressor (LacI) to systematically map and engineer alternate allosteric communication, in several LacI/GalR homologues. Answering the fundamental question of whether allostery in the broader LacI/GalR family has been evolved to be controlled by a set of conserved residues or whether the protein is plastic and predisposed to allostery across different residue sequences will ultimately give insights into allosteric structure-function relationships and aid in the engineering of novel transcription factors. Mapping allostery and determining the evolutionary origin, links, and mechanism by which allostery is conferred in the LacI/GalR family will provide crucial knowledge into how other proteins may be designed to exhibit allostery and how to control and modulate allostery in existing systems. Upon completion, this study will enable scientist to test assertions with regard to the origin and molecular mechanics of alternate allosteric communication via the development of design rules for specific allosteric operations. In turn this algorithm will produce novel LacI/GalR-based transcription factors for use in a broad range of biotechnological applications. This project is co-funded by the Molecular Biophysics and the Systems and Synthetic Biology programs of the Division of Molecular and Cellular Biosciences.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.

该项目旨在了解和预测转化基因的蛋白质（即转录因子）如何开发出处理信息并与附近环境相互作用的手段。蛋白质过程信号信息的机制称为变构通信。尽管对变构传播的研究已经进行了四十年以上，但这些基本过程的关键细节仍然很少了解。知识的差距使科学家和工程师无法设计具有定制沟通能力的新蛋白质。因此，当前项目的重点是阐明将使科学家能够在处理广泛信号的转录因素中建立变构沟通的规则。这项研究将扩大科学社区对变构沟通的理解，并使可以使用可用于使社会的新工具的开发（例如，用于生物工业应用的新且价格较低的过程控制以及用于个性化医学的系统）。此外，该项目将涉及下一代科学家，特别是博士学位的培训和教育。水平的研究生。蛋白质变构是一种至关重要的蛋白质功能，已被证明是在分子水平上理解的一个烦人的问题。变构通信是用于控制基因表达的许多转录因子的标志，并使合成生物学家能够重新编程细胞。这项研究的具体目标是利用乳糖阻遏物（LACI）的基本结构和功能关系，以系统地绘制和工程师在几种LACI/GALR同源物中进行替代变构通信。回答较宽的LACI/GALR家族中的变构的基本问题是否已进化为由一组保守的残留物来控制，或者该蛋白质是否是塑料的，并且偏见于不同残基序列的变构，最终将洞悉变形结构 - 函数 - 功能 - 函数 - 函数函数关系和在新型转录因素的工程中的帮助。绘制变构和确定在LACI/GALR家族中赋予变构的进化起源，链接和机制将提供至关重要的知识，以表明如何设计其他蛋白质以表现出变构以及如何控制和调节现有系统中的变构。完成后，这项研究将使科学家能够通过为特定的变构操作制定设计规则来测试有关替代变构通信的起源和分子力学的主张。反过来，该算法将产生新颖的基于LACI/GALR的转录因子，以在广泛的生物技术应用中使用。该项目由分子生物物理学以及分子和细胞生物科学划分的系统和合成生物学计划共同资助。该奖项反映了NSF的法定任务，并被认为值得通过基金会的知识分子优点和更广泛的影响标准通过评估来进行评估。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bioinspired Green Science and Technology Symposium in NYC

纽约仿生绿色科技研讨会

DOI：
10.1016/j.matt.2022.06.031
发表时间：
2022
期刊：
Matter
影响因子：
18.9
作者：
Alcantar, Norma A.;Banta, Scott;Cak, Anthony D.;Chen, Xi;DelRe, Christopher;Deravi, Leila F.;Dordick, Jonathan S.;Giebel, Brian M.;Greenfield, Dianne;Groffman, Peter M.
通讯作者：
Groffman, Peter M.

What Needs to Change in Academia to Increase the Number of Black Scientists and Engineers? A Son of Redlines.

学术界需要做出哪些改变才能增加黑人科学家和工程师的数量？