STRUCTURE/FUNCTION OF CH DOMAIN PROTEINS

描述：Calponin-Homology（CH）结构域识别了一个新的超级 整合细胞骨架的细胞骨架蛋白家族， 信号通路基于来自钙调蛋白的小肌动蛋白结合结构域， CH结构域作为靶向各种蛋白质的模块发挥作用 包括信号蛋白，vav和IQGAP，以及肌动蛋白交联 蛋白质到肌动蛋白丝。最近，CH结构域被发现于 IFAPs plectin和BPAB 1 n1（肌张力障碍蛋白）表明它们连接了 肌动蛋白和中间丝细胞骨架。CH的广泛使用 重要的结构和信号系统中的结构域可以提供直接的 调节细胞结构的细胞机制。了解CH如何 结构域蛋白组织细胞骨架，这个建议有三个 明确的目标。第一个目标是描述交叉机制 通过确定纤维蛋白-肌动蛋白交叉的3D结构， 并通过识别结合界面处的相互作用残基， 定点诱变这种结构将作为一种模式， 了解CH结构域蛋白如何结合肌动蛋白细胞骨架。的 第二个目的是描述纤维蛋白-波形蛋白复合物的功能， 细胞基质粘附位点。肌动蛋白和IF之间的相互作用 细胞骨架可能在组装和/或稳定性中起重要作用 一个细胞附着。最后一个目的是确定钙调蛋白的功能 通过生物化学和遗传学的结合。单纯 缺乏肌肉收缩系统的酵母细胞骨架，钙调蛋白 应该更能代表它在非肌肉细胞中的功能。的 申请人指出，对CH结构域蛋白的研究直接 与理解疾病的潜在机制有关。致癌 VAV的性质、肌强直性肌张力障碍的发作、血液疾病和 肌营养不良症是由CH的不同成员的缺陷引起的。 域超家族

DESCRIPTION: The Calponin-Homology (CH) domain identifies a new super family of cytoskeletal proteins that integrate the cytoskeleton and signalling pathways. Based on a small actin binding domain from calponin, the CH domain functions as a module that targets various proteins including signaling proteins, vav and IQGAP, and actin crosslinking proteins to actin filaments. More recently, CH domains were discovered in the IFAPs plectin and BPAB1n1 (dystonin) suggesting that they connect the actin and intermediate filament cytoskeletons. This widespread use of CH domains in important structural and signaling systems may provide a direct cellular mechanism for regulating cell structure. To understand how CH domain proteins organize the cytoskeleton, this proposal has three specific aims. The first goal is to describe the mechanism of cross linking by fibrin by determining the 3D structure of a fimbrin-actin cross link and by identifying interacting residues at the binding interface by site directed mutagenesis. This structure will serve as a model for understanding how CH domain proteins bind the actin cytoskeleton. The second aims to describe the function of the fibrin-vimentin complex at cell substratum adhesion sites. Interactions between the actin and IF cytoskeleton may play in important role in the assembly and/or stability of a cell attachment. The last aim is to identify the function of calponin by a combination of biochemical and genetic approaches. In the simple cytoskeleton of yeast which lacks the muscle contractile system, calponin should more closely represent its function in non-muscle cells. The applicant points out that studies on CH domain proteins are directly relevant to understanding underlying mechanisms of disease. The oncogenic properties of vav, the onset of myotonic dystony, blood disorders, and muscular dystrophy are caused by defects in different members of the CH domain superfamily.