NSF-BSF: Unraveling the molecular determinants of protein oligomerization

NSF-BSF：揭示蛋白质寡聚化的分子决定因素

• 批准号: 2032315
• 负责人: Eric Gaucher
• 金额: $ 120万
• 依托单位: Georgia State University Research Foundation, Inc.
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2032315&HistoricalAwards=false
• 关键词: NSF; BSF; Unraveling; molecular; determinants

The complexity of life is predicated on the ability of biomolecules to organize themselves into higher-order functional structures. This project will investigate how evolutionary processes shape the ability of individual proteins to self-assemble into complex structures that then generate new biomolecular functionalities than possible for the individual proteins themselves. Insights gained from this research will be useful for protein engineering attempts to create de novo or expanded functionalities of enzymes and other structural proteins. The project will also provide support and resources for K-12 teachers to enhance STEM participation in a socioeconomically challenged section of Atlanta (Clayton Co.). We anticipate that stronger research literacy at the teacher level will generate greater interest and participation of K-12 students in STEM activities such as science fairs, resulting in better preparation for post-secondary education.This project will specifically focus on methionine S-adenosyltransferases (MATs), an essential homo-tetrameric enzyme of central metabolism characterized by high variability in quaternary structure integrity among its homologs. The research will assess thermodynamics and kinetics of MAT folding and (dis)assembly, folding dependency of individual MAT subunits on molecular chaperones, aggregation propensity of intermediate MAT sub-complexes, and the intracellular turnover and activity of assembled MAT complexes. Comparative analysis of extant sequences will be complemented with ancestral sequence reconstruction of the intermediate steps linking ancestral and derived states. The project will generate bacterial strains in which genes encoding the endogenous MAT homomers are replaced with extant or ancestrally reconstructed orthologs, subject the strains to laboratory evolution in a variety of environmental conditions, and identify the genetic, structural, functional and systems determinants of adaptation as best possible given the constraints of laboratory evolution. Through this multifaceted approach, the project will enable a genotype-phenotype-fitness connection for homomer evolution.This project is jointly funded by the Genetic Mechanisms an.d Molecular Biophysics programs of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.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.

生命的复杂性是建立在生物分子将自己组织成高阶功能结构的能力之上的。该项目将研究进化过程如何塑造单个蛋白质自组装成复杂结构的能力，然后产生比单个蛋白质本身可能产生的新的生物分子功能。从这项研究中获得的见解将有助于蛋白质工程尝试创造新的或扩展酶和其他结构蛋白的功能。该项目还将为K-12教师提供支持和资源，以提高亚特兰大（克莱顿公司）社会经济困难地区的STEM参与程度。我们预计，教师水平上更强的研究素养将激发K-12学生对科学博览会等STEM活动的更大兴趣和参与，从而为接受高等教育做好更好的准备。该项目将特别关注蛋氨酸s -腺苷转移酶（MATs），这是一种重要的中心代谢同型四聚体酶，其同源物之间的四级结构完整性具有高度可变性。该研究将评估MAT折叠和（反）组装的热力学和动力学，单个MAT亚基对分子伴侣的折叠依赖性，中间MAT亚复合物的聚集倾向，以及组装的MAT复合物的细胞内周转和活性。现有序列的比较分析将与连接祖先和衍生状态的中间步骤的祖先序列重建相辅相成。该项目将产生细菌菌株，其中编码内源性MAT同源物的基因被现有或祖先重建的同源物取代，使菌株在各种环境条件下进行实验室进化，并在实验室进化的约束下尽可能确定适应的遗传，结构，功能和系统决定因素。通过这种多方面的方法，该项目将使同源体进化的基因型-表型-适应度连接成为可能。这个项目是由遗传机制和。d生物科学理事会分子和细胞生物科学部的分子生物物理学项目。这个美国/以色列合作项目由美国国家科学基金会和以色列两国科学基金会支持。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。