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: 10216284
• 负责人: Naomi Courtemanche
• 金额: $ 28.65万
• 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 2022-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216284
• 关键词: Actins; Address; Affect; Automobile Driving; Binding; Biological; Biological Assay; Biological Process; Biophysics; Bundling; Cell Proliferation; Cell Shape; Cell division; Cell physiology; Cells; Complex; DNA; Development; Diffusion; Dilated Cardiomyopathy; Disease; Equilibrium; Filament; Filopodia; Fluorescence Resonance Energy Transfer; Focal Adhesions; Genes; Growth; In Vitro; Malignant Neoplasms; Mammals; Mediating; Microcephaly; Microfilaments; Modeling; Molecular; Mutation; Nuclear; Play; Polymers; Positioning Attribute; Process; Property; Protein Family; Protein Isoforms; Proteins; Role; Saccharomycetales; Signal Transduction; Stress Fibers; Structure; Techniques; Testing; Thick; Variant; Work; base; cell motility; cofilin; disease-causing mutation; flexibility; human disease; insight; mechanical force; parallel architecture; physical property; polymerization; profilin; scaffold

PROJECT SUMMARY Cells dynamically assemble a diverse set of actin-based structures to perform essential processes including motility, division and signaling. One class of actin structures consists of networks of actin filaments that are bundled together into parallel or anti-parallel architectures. These bundled actin structures include contractile rings, actin cables, filopodia, and the stress fibers that promote focal adhesion maturation and nuclear positioning. The actin filaments that comprise these structures are primarily polymerized by formins, a family of proteins that nucleate and direct the elongation of unbranched actin filaments. Mammals express 15 formin isoforms, each of which possesses unique actin assembly properties and plays a specific role in cells. Although mutations in formin genes are associated with a number of human diseases including preleukemic disorders and cancer, it remains unknown how the polymerization activity of each formin isoform is tuned for the assembly of a specific bundled actin structure and participation in a specific cellular process. To bridge this gap in understanding, we must establish how formins function in the context of the bundled actin structures that exist in cells. We will address this question by characterizing the mechanism of formin-mediated assembly of bundled actin structures. Our central hypothesis is that incorporation of formin-bound actin filaments into bundled structures modulates polymerization by exposing formins to force, filament bundling and filament severing. We will use a combination of biophysical and cell biological approaches to test this hypothesis by pursuing three specific aims: (1) To elucidate the effects of force on the mechanism of formin-mediated filament elongation, (2) to investigate the relationship between filament bundling and formin polymerization activity, and (3) to evaluate the contribution of filament turnover to bundled actin structure assembly. By establishing the mechanism of formin-directed bundled actin assembly, we will gain fundamental insights into the large number of cellular processes regulated by formins. This work will also provide a molecular basis for understanding how formins contribute to healthy cellular proliferation and normal development.

项目摘要 细胞动态组装一组基于肌动蛋白的结构，以执行基本过程 运动，分裂和信号传导。一类肌动蛋白结构由肌动蛋白网络组成 捆绑在一起成平行或反行架构。这些捆绑的肌动蛋白结构包括收缩 环，肌动蛋白电缆，丝状肌以及促进局灶性粘附成熟和核的压力纤维 定位。构成这些结构的肌动蛋白丝主要由formins聚合，一个家族 蛋白质成核并指导未分支肌动蛋白丝的伸长。哺乳动物表达15 同工型，每种都具有独特的肌动蛋白组装特性，并在细胞中起特定的作用。 虽然formin基因的突变与包括普雷克血症在内的多种人类疾病有关 疾病和癌症，尚不清楚如何调整每种形式的同工型的聚合活性 特定捆绑肌动蛋白结构的组装并参与特定的细胞过程。桥接这个 理解差距，我们必须确定formins在捆绑肌动蛋白结构的背景下如何发挥作用 在细胞中存在。我们将通过表征形式介导的组装机制来解决这个问题 捆绑的肌动蛋白结构。我们的核心假设是将结合肌动蛋白丝的结合到 捆绑结构通过将造型暴露于强力，丝捆和细丝来调节聚合 切断。我们将使用生物物理和细胞生物学方法的组合来检验该假设 追求三个特定的目标：（1）阐明力对formin介导的机制的影响 细丝伸长，（2）研究细丝捆绑与甲素聚合之间的关系 活性和（3）评估细丝周转对捆绑肌动蛋白结构组件的贡献。经过 建立形成指导捆绑肌动蛋白组件的机制，我们将获得基本的见解 由formins调节的大量细胞过程。这项工作还将为 了解肌肉如何有助于健康的细胞增殖和正常发育。