Organization of transcriptional machinery by weak multivalent interactions

通过弱多价相互作用组织转录机制

• 批准号: 10758297
• 负责人: Benjamin Sabari
• 金额: $ 2.55万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758297
• 关键词: Biological Assay; Biological Process; Cell Differentiation process; Cell Nucleus; Cell model; Data; Defect; Development; Developmental Process; Disease; Educational process of instructing; Gene Activation; Genes; Genetic Transcription; Goals; Investigation; Mediating; Modeling; Process; Protein Region; Reporter; Role; Smooth Muscle Myocytes; Time; Transcription Coactivator; Work; functional outcomes; genomic locus; human disease; insight; myocardin; novel; parent grant; protein protein interaction; recruit

Project Summary Weak multivalent interactions mediated by intrinsically disordered regions (IDRs) of proteins have been proposed to spatially organize the transcriptional machinery into multi-component clusters, yet we know little about how these IDRs interact with specific partners to enable functional outcomes. As these interactions are highly dynamic and cluster-dependent they have been overlooked by conventional strategies to identify protein-protein interactions. Our preliminary data support our overarching hypothesis that in the context of higher-order clusters weak multivalent interactions are capable of highly specific hetero-typic interactions leading to functional organization of the nucleus. Our long-term objective is to understand how weak multivalent interactions organize specific components of the transcriptional machinery in order to enable gene activation. The objective of the parent grant is to investigate the mechanism and function of cluster-mediated interactions of IDR of found on transcriptional coactivators. The proposed work in the diversity supplement focusses on investigating myocardin (MYOCD), a smooth muscle cell specific coactivator. The proposed work is directly related to Aim 3 of the parent grant, which proposes to investigate the functional role of coactivator IDRs in various models of gene activation including reporter assays and cell models of cellular differentiation. MYOCD is a smooth muscle cell specific coactivator, and we will be investigating the role of its IDR in reporter assays and smooth muscle cell differentiation. Completion of these studies will advance the goals and objectives of the parent grant and will teach us about how the function of prevalent yet often overlooked IDRs in gene activation.

项目摘要 已经提出了由蛋白质固有无序区(IDR)介导的弱多价相互作用 在空间上将转录机制组织成多组分的集群，但我们对如何 这些IDR与特定的合作伙伴互动，以实现职能成果。因为这些相互作用是高度 传统的鉴定蛋白质-蛋白质的策略忽视了它们的动态和依赖于簇的特性 互动。我们的初步数据支持我们的主要假设，即在更高阶星系团的背景下 弱多价相互作用能够产生高度特异性的异型相互作用，从而导致功能性 原子核的组织。我们的长期目标是了解弱多价相互作用是如何组织的 转录机制的特定组成部分，以实现基因激活。该计划的目标是 父母资助的目的是研究发现的IDR的簇间相互作用的机制和功能 转录辅活化子。多样性补编中拟议的工作重点是调查心肌梗死 肌萎缩侧索硬化症(MYOCD)，一种平滑肌细胞特异性辅助激活因子。拟议的工作与家长的目标3直接相关 Grant，他建议研究辅助激活因子IDRs在各种基因激活模型中的功能作用 包括报告分析和细胞分化的细胞模型。肌萎缩侧索硬化症是一种特殊的平滑肌细胞 辅活化子，我们将研究其IDR在报告分析和平滑肌细胞中的作用 差异化。完成这些研究将推进父母赠款的目标和目的，并将 告诉我们普遍存在的IDR在基因激活中的作用，但常常被忽视。