PROTEIN INTERACTIONS REGULATING CELL MOTILITY

描述：（改编自应用程序）这项工作的长期目标是 了解定向细胞运动的结构和生化基础。 许多细胞有能力移动或改变它们的形状，以响应 外部信号。这种运动，发生在发展过程中，免疫 反应和侵袭性肿瘤的形成是由肌动蛋白的重塑介导的。 细胞骨架为了在空间和时间上精确地运动，外部 信号必须被解释并用于建立电池极性。肌动蛋白 聚合必须专门针对细胞的前缘， 它可以为膜的突出提供机械向前的力。一类 衔接蛋白，包括Enabled（Ena），血管扩张刺激蛋白 （VASP）和Wiscott-Aldrich综合征蛋白（WASP）在 控制肌动蛋白聚合。这些蛋白质定位于潜在的主导 通过与上游信号蛋白相互作用的边缘位点。后来他们 被认为是募集肌动蛋白下游成分的支架 聚合机械 Lim博士选择专注于这些衔接蛋白及其相互作用， 为了了解它们是如何本地化的，以及它们如何充当开关， 激活肌动蛋白聚合。他的大部分努力将用于 在这些蛋白质中发现的保守识别模块，称为使能VASP 同源1（EVH 1）结构域。EVH 1结构域在初始的免疫应答中起核心作用。 面向.他剩下的努力将致力于了解 这些蛋白质随后激活肌动蛋白聚合。他会用一个 生物物理学、结构学和细胞生物学方法的组合， 实现以下具体目标： (1)阐明使能的VASP同源1（EVH 1）域 特异性识别受体中发现的富含脯氨酸的基序; (2)确定EVH 1域是否为通用双重识别模块， 结合磷脂和肽; (3)确定EVH 1结构域在靶向和极性中的作用 体内建立; (4)阐明了开关行为的结构和能量基础， 神经元WASP

Description: (Adapted from the application) The long term goal of this work is to understand the structural and biochemical basis of directed cell movement. Many cells have the ability to move or alter their shapes in response to external signals. Such movements, which occur during development, immune response, and invasive tumor formation, are mediated by remodeling of the actin cytoskeleton. For spatially and temporally precise movements to occur, external signals must be interpreted and used to establish cell polarity. Actin polymerization must be specifically targeted to the cell's leading edge where it can provide the mechanical forward force for membrane protrusion. A class of adapter proteins, which include Enabled (Ena), vasodilator stimulated protein (VASP) and Wiscott-Aldrich Syndrome Protein (WASP), plays a central role in controlling actin polymerization. These proteins localize to potential leading edge sites via interactions with upstream signaling proteins. Subsequently they are thought to act as scaffolds to recruit downstream components of the actin polymerization machinery. Dr. Lim has chosen to focus on these adapter proteins and their interactions in order to understand how they are localized and how they act as switches to activate actin polymerization. Much of his effort will be directed towards a conserved recognition module found in these proteins, known as the Enabled VASP Homology 1 (EVH1) domain. EVH1 domains play a central role in initial targeting. The remainder of his effort will be directed at understanding how these proteins subsequently activate actin polymerization. He will use a combination of biophysical, structural, and cell biological approaches to address the following specific aims: (1) Elucidate the mechanism by which the Enabled VASP Homology 1 (EVH1) domain specifically recognizes proline-rich motifs found in receptors; (2) Determine if EVH1 domains are general dual recognition modules that can bind both phospholipids and peptides; (3) Determine the role of the EVH1 domain in targeting and polarity establishment in vivo; (4) Elucidate the structural and energetic basis of switching behavior in neuronal WASP.