Molecular mechanisms of bundled actin structure assembly by formins

福明组装成束肌动蛋白结构的分子机制

• 批准号: 10585189
• 负责人: Naomi Courtemanche
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585189
• 关键词: Actins; Architecture; Binding; Binding Sites; Biological; Biological Process; Biophysics; Bundling; Cardiomyopathies; Cell physiology; Cells; Complex; Cytoskeleton; Dilated Cardiomyopathy; Disease; Engineering; Equilibrium; Family; Filament; Genes; Goals; Grant; Growth; Higher Order Chromatin Structure; Human Development; In Vitro; Individual; Investigation; Kidney Diseases; Length; Light; Link; Malignant Neoplasms; Mammals; Maps; Mediating; Methodology; Microcephaly; Microfilaments; Molecular; Morphology; Mutation; Pathology; Physiological; Physiology; Play; Polymers; Process; Property; Protein Family; Protein Isoforms; Proteins; Reaction; Regulation; Research; Role; Saccharomycetales; Series; Shapes; Structure; Testing; Thick; Visualization; Work; cell motility; cofilin; crosslink; design; flexibility; genetic regulatory protein; human disease; insight; migration; molecular pathology; nervous system disorder; physical property; polymerization; profilin; reconstitution

PROJECT SUMMARY The goal of this research is to understand how formins shape the architecture and dynamics of the actin cytoskeleton. Formins are a uniquely versatile family of actin regulatory proteins that stimulate both filament nucleation and elongation. Actin filaments assembled by formins are incorporated into a diverse set of higher- order structures that support essential cellular functions, including migration, division, and transport. Mammals express 15 formin isoforms, each of which possesses unique actin assembly properties and plays a specific role in cells. Consistent with this specialization, mutations in individual formin genes are linked to a broad range of diseases and pathologies, including neurological disorders, kidney disease, microcephaly, cardiomyopathy, and several cancers. However, despite their foundational roles as regulators of actin assembly, it is unknown how the polymerization activity of each formin isoform is tailored for the assembly of a specific actin structure. To bridge this gap in understanding, our goal is to establish how the broad range of formin activities influences actin network physiology and dynamics. Our central hypothesis is that formins direct the assembly and specialization of higher-order actin structures by generating binding sites for bundling and severing proteins at isoform-specific rates. We will use a combination of biophysical and cell biological approaches to test this hypothesis by pursuing three specific aims: (1) to elucidate the mechanism that underpins the adaptable polymerization activities of formins, (2) to investigate the effects of formin-mediated elongation on actin filament bundling, and (3) to assess the interdependent contributions of filament nucleation, elongation, and turnover to actin structure dynamics. Our work will establish at a molecular level how formins dynamically regulate the construction, specialization, and function of cytoskeletal structures that are essential for cellular viability and human development. In light of the diversity of formin isoforms, our results will generate fundamental insights into the molecular and temporal regulation of a large number of cellular processes. This will inform and guide our understanding of the molecular pathologies underlying a diverse set of human diseases linked to mutations in formin genes.

项目概要 这项研究的目的是了解formins如何塑造肌动蛋白的结构和动力学 细胞骨架。福尔明是一个独特的多功能肌动蛋白调节蛋白家族，可以刺激肌动蛋白丝 成核和伸长。由福尔明组装的肌动蛋白丝被纳入多种高级结构中。 支持基本细胞功能的秩序结构，包括迁移、分裂和运输。哺乳动物 表达 15 种福尔米亚型，每种亚型都具有独特的肌动蛋白组装特性，并发挥特定的作用 在细胞中的作用。与这种专业化相一致，个体福明基因的突变与广泛的 一系列疾病和病理，包括神经系统疾病、肾脏疾病、小头畸形、 心肌病和多种癌症。然而，尽管它们作为肌动蛋白调节剂的基础作用 组装时，尚不清楚每个亚型同种型的聚合活性如何针对组装 特定的肌动蛋白结构。为了弥合这种理解上的差距，我们的目标是确定广泛的 福尔明活动影响肌动蛋白网络的生理学和动力学。我们的中心假设是形成直接 通过生成用于捆绑的结合位点来组装和特化高阶肌动蛋白结构 以异构体特异性速率切割蛋白质。我们将结合生物物理学和细胞生物学 通过追求三个具体目标来检验这一假设的方法：（1）阐明 支持福尔明的适应性聚合活性，(2) 研究福尔明介导的影响 肌动蛋白丝成束的伸长，以及（3）评估丝成核的相互依赖的贡献， 伸长和肌动蛋白结构动力学的更新。我们的工作将在分子水平上确定福尔摩斯如何 动态调节重要的细胞骨架结构的构建、专业化和功能 用于细胞活力和人类发育。鉴于福尔米亚型的多样性，我们的结果将产生 对大量细胞过程的分子和时间调节的基本见解。这 将告知并指导我们对不同人类的分子病理学的理解 与福尔明基因突变有关的疾病。