Dynamic Regulation of the Actin Filament Barbed End

肌动蛋白丝刺端的动态调节

• 批准号: 10590667
• 负责人: David Sept
• 金额: $ 29.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590667
• 关键词: Acetylation; Actins; Address; Adopted; Affect; Behavior; Binding Proteins; Biochemical; Biochemistry; Biophysics; Cell division; Cell physiology; Cells; Cellular biology; Complex; Cryoelectron Microscopy; Cytoskeleton; Data; Disease; Endocytosis; Eukaryotic Cell; Filament; In Vitro; Knowledge; Learning; Lysine; Methylation; Microfilaments; Molecular; Molecular Conformation; Names; Normal Cell; Nucleotides; Plus End of the Actin Filament; Polymers; Post-Translational Protein Processing; Process; Proteins; Protomer; Regulation; Role; Series; Structure; Work; cell motility; in vivo; member; myotrophin; polymerization; prevent; protein function; simulation

Project Summary Actin is a key protein for normal cell function, and the ability to control the polymerization of actin filaments is essential in the cell. Actin assembles into filaments with two distinct ends, and most of this control happens at what is termed the plus or barbed end of the filament. Two key proteins function at the barbed end: capping protein and formins. As suggested by its name, capping protein “caps” the barbed end and prevents further polymerization, but the activity of capping protein is also regulated by the action of proteins such as myotrophin/V-1, CARMIL and twinfilin. Formins have the opposite effect of capping protein and enhance polymerization at the barbed end. However, just as capping protein is regulated, the function of the formin INF2 is modulated by cyclase-associated protein (CAP) as well as post-translational modifications to actin. The focus of this proposal is to understand the structural, dynamical and functional mechanisms that regulate the barbed end of the filament. Through a combination of computational, in vitro and in vivo studies we will: (a) gain new understanding of what defines the barbed end and how it is affected by the nucleotide state of actin; (b) learn how capping protein interacts with the barbed end and how this interaction is affected by the steric and allosteric effects of V-1, CARMIL and twinfilin; and (c) determine how INF2 interacts with the barbed and how both CAP and lysine methylation of actin alter this interaction.

项目概要 肌动蛋白是正常细胞功能的关键蛋白质，能够控制肌动蛋白的聚合 肌动蛋白丝在细胞中至关重要，可以组装成具有两个不同末端的丝状体。 大部分控制发生在灯丝的正端或倒刺端，两个键。 蛋白质在有刺的末端起作用：加帽蛋白质和福尔明，正如其名称所暗示的那样。 加帽蛋白“盖住”有刺的末端并防止进一步聚合，但其活性 加帽蛋白还受肌营养蛋白/V-1、CARMIL 和 Twinfilin 具有封盖蛋白质的相反作用并增强聚合。 然而，正如加帽蛋白受到调节一样，formin INF2 的功能也受到调节​​。 由环化酶相关蛋白 (CAP) 以及翻译后修饰调节 肌动蛋白。 该提案的重点是了解结构、动力和功能机制 通过计算、体外的结合来调节细丝的倒刺末端。 和体内研究，我们将：（a）对带刺末端的定义以及如何定义有新的理解 它受到肌动蛋白核苷酸状态的影响；（b）了解加帽蛋白如何与肌动蛋白相互作用。 带刺末端以及这种相互作用如何受到 V-1 的空间和变构效应的影响， CARMIL 和 twinfilin；以及 (c) 确定 INF2 如何与 Barbed 相互作用以及 CAP 如何相互作用 肌动蛋白的赖氨酸甲基化改变了这种相互作用。