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.

项目摘要 肌动蛋白是正常细胞功能的关键蛋白质，并且能够控制聚合的能力 肌动蛋白丝在细胞中至关重要。肌动蛋白组装成具有两个不同末端的细丝，并且 大多数控制发生在灯丝的正末端或带刺的末端。两个键 蛋白质在带刺端的功能：封端蛋白质和造型。如其名称所建议的 限额蛋白质“盖”刺尾端并防止进一步的聚合，但是 封闭蛋白还受蛋白质（例如肌营养素/V-1，Carmil和Carmil和 双胞胎。甲素具有封盖蛋白质的相反作用，并增强了聚合在 带刺的末端。但是，正如调节封盖蛋白一样，formin inf2的功能为 由环酶相关蛋白（CAP）以及翻译后修饰调节至 肌动蛋白。 该建议的重点是了解结构，动态和功能机制 调节钢丝的带刺的末端。通过计算，体外的结合 在体内研究中，我们将：（a）对定义刺端的原因以及如何获得新的了解 它受肌动蛋白的核苷酸状态的影响； （b）了解上限蛋白如何与 带刺的端以及这种相互作用如何受到V-1的空间和变构影响的影响 Carmil和Twinfilin; （c）确定INF2如何与刺与刺之间的相互作用以及两个盖子如何相互作用 肌动蛋白的赖氨酸甲基化改变了这种相互作用。