Structural and Functional Studies of Molecular Machines Involved in Chemical Modifications of Macromolecules

参与大分子化学修饰的分子机器的结构和功能研究

• 批准号: 10276853
• 负责人: Minglei Zhao
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276853
• 关键词: ADP ribosylation; Address; Adopted; Biology; COVID-19 pandemic; Chemicals; Complex; Disease; Drug resistance; Enzymes; Eukaryotic Cell; Genes; Goals; Human; Influenza vaccination; Innate Immune Response; Link; Malignant Neoplasms; Methods; Modification; Molecular; Molecular Biology; Molecular Machines; Mutation; Neurodegenerative Disorders; Play; Process; Protein Engineering; Proteins; Ribonucleoproteins; Role; Structure; System; Transcriptional Regulation; Translational Regulation; Ubiquitin; Ubiquitination; base; cofactor; human disease; inhibitor/antagonist; insight; macromolecule; major vault protein; particle; proteostasis; response; structural biology; tool; vaccine development

PROJECT SUMMARY / ABSTRACT Our lab focuses on structural and functional studies of molecular machines involved in chemical modifications of macromolecules. Naturally occurring chemical modifications of macromolecules play essential roles in all aspects of molecular biology, from transcriptional and translational regulation to functional modulation of various proteins. Misregulation of the chemical modifications is involved in many human diseases such as cancers and neurodegenerative diseases. Although many have been described and characterized, there are still significant amounts of chemical modification systems that are poorly understood. Our long term goal is to elucidate the structure and function of molecular machines involved in various chemical modification systems and develop new tools and strategies to modulate their activity against the relevant diseases based on what we have learned. In the next five years, we will be focusing on two systems, the p97 related ubiquitination system and the Vault related ADP-ribosylation system. More than thirty mutations of human p97 have been identified, which are associated with a number of neurodegenerative diseases. The molecular mechanism, however, remains elusive. Through structural biology approaches and protein engineering, we will address 1) how p97 processes ubiquitin chains of different topologies through the cofactors; 2) the structural and functional consequences of disease mutations; 3) the mechanism of inhibitors of p97 and its cofactors. Our efforts promise unprecedented insights into the function of p97, a central hub of cellular protein homeostasis. Vault is the largest ribonucleoprotein in eukaryotic cells with a unique structure. The function of Vault has been linked to drug resistance in cancer and innate immune response. Recently, major vault protein (MVP) was identified as one of the 9 marker genes that can predict influenza vaccination responses. Given the importance of vaccine development during this COVID-19 pandemic, a deep understanding of Vault’s molecular mechanism is critical. We are going to focus on PARP4, the only enzyme in the Vault complex catalyzing ADP-ribosylation. Elucidating the function of PARP4 and how it interacts with Vault particle is the key to understand the molecular function of Vault.

项目摘要 /摘要 我们的实验室专注于参与化学的分子机器的结构和功能研究 大分子的修饰。 从转录和翻译调节到功能调制的分子生物学各个方面的作用 各种蛋白质的变化涉及许多人类疾病 癌症和神经退行性疾病。 我们的长期目标是大量的化学修饰系统。 阐明参与各种化学修饰系统的分子机的结构和功能 并制定新的工具和策略，以模块有关wee的相关探索贝斯 在接下来的五年中，我们将专注于两个系统 和与金库相关的ADP-核糖基化系统。 已经确定了人类p97的三十多个突变，这与许多 然而，神经退行性疾病 方法和蛋白质工程，我们将解决1）P97如何处理不同的泛素链 通过辅助因子的拓扑结构； p97抑制剂的机制是我们的辅助因素。 P97，细胞蛋白稳态的中心枢纽。 保管库是具有独特结构的真核细胞中最大的核糖核蛋白。 与癌症和先天免疫反应中的耐药性有关。 考虑到重要性。 疫苗发育期间在这一covid-19大流行期间，对保险库的分子机制有深刻的理解 是至关重要的。 阐明PARP4的功能及其与金库粒子的相互作用是理解分子的 保险库的功能。