Protein Disorder as a Mechanism of RNA Binding and Regulation

蛋白质紊乱作为 RNA 结合和调节的机制

• 批准号: 10671499
• 负责人: Daniel Issac Dominguez
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671499
• 关键词: Area; Binding; Binding Proteins; Biochemical; Cells; Cellular biology; Data; Disease; Disease Pathway; Event; Gene Expression; Genomic approach; Guanine; Literature; Mediating; Pathogenicity; Pathway interactions; Proteins; RNA; RNA Binding; RNA Folding; RNA Processing; RNA Recognition Motif; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Regulator Genes; Research; Role; Structure; Work; programs; protein folding; protein protein interaction

Project Abstract As factors involved in all aspects of RNA processing, RNA binding proteins (RPBs) are master regulators of gene expression. Despite this critical role, gaps remain in our understanding of how RBPs interact with RNA. Generally, RBPs have been considered to interact with typically single-stranded RNA via folded RNA-binding domains. However, many RBPs also have inherently disordered domains of low compositional complexity (low complexity domains, LCDs). In our current understanding of how RBPs interact with RNA, LCDs mediate protein- protein interactions and/or weak, non-specific RNA interactions. In contrast, a growing body of literature, and our own data, indicate LCDs are capable of specific binding to highly stable guanine-based helical RNA structures. These findings represent a reversal of the canonical binding mode: rather than folded protein binding to unstructured RNA, we have observed folded RNA binding to unstructured protein. My research program asks i) how do RBP LCDs interact with RNA? And, ii) what are the functional consequences of LCD-RNA interactions? This proposal outlines my research program to decipher basic mechanisms and dynamics of RBP-RNA interactions and define their role in normal and pathogenic pathways combining unbiased biochemical approaches with cell-based genomic strategies. Data generated from the proposed research will contribute broadly across all areas of cell biology by illuminating a more complete picture of RBP-RNA interactions.

项目摘要 RNA结合蛋白（RNA binding proteins，RPB）是RNA加工的主要调控因子，参与RNA加工的各个环节。 基因表达。尽管有这种关键作用，但我们对RBP如何与RNA相互作用的理解仍然存在差距。 通常，RBP被认为通过折叠的RNA结合与典型的单链RNA相互作用 域.然而，许多RBP还具有低组成复杂性（低的分子量）的固有无序结构域。 复杂域（LCD）。在我们目前对RBP如何与RNA相互作用的理解中，LCD介导蛋白质- 蛋白质相互作用和/或弱的非特异性RNA相互作用。相反，越来越多的文学作品，以及我们的 我们自己的数据表明，LCD能够特异性结合高度稳定的基于鸟嘌呤的螺旋RNA结构。 这些发现代表了典型结合模式的逆转：而不是折叠蛋白结合到 在非结构化的RNA中，我们观察到折叠的RNA与非结构化的蛋白质结合。我的研究计划要求我） RBP LCD如何与RNA相互作用？以及，ii）LCD-RNA相互作用的功能后果是什么？ 这个建议概述了我的研究计划，以破译RBP-RNA的基本机制和动力学 相互作用，并确定它们在正常和致病途径中的作用， 基于细胞的基因组策略。从拟议的研究产生的数据将有助于 通过阐明RBP-RNA相互作用的更完整的图片，广泛地跨越细胞生物学的所有领域。