STRUCTURE/FUNCTION OF CH DOMAIN PROTEINS

描述：Calponin同源(CH)结构域识别一种新的超级 整合细胞骨架和细胞骨架的细胞骨架蛋白家族 信号通路。基于来自Calponin的一个小的肌动蛋白结合域， CH结构域的功能是以各种蛋白质为靶标的模块 包括信号蛋白、VaV和IQGAP，以及肌动蛋白交联 从蛋白质到肌动蛋白细丝。最近，在中国发现了CH域 IFAPs plectin和BPAB1n1(Dysttin)提示它们连接 肌动蛋白和中间丝细胞骨架。CH的广泛使用 在重要的结构和信号系统中的域可能提供直接的 调节细胞结构的细胞机制。要了解中国是如何 结构域蛋白组织细胞骨架，这个提议有三个 明确的目标。第一个目标是描述交叉的机制。 纤维蛋白通过确定纤毛蛋白-肌动蛋白交叉的三维结构进行连接 并通过鉴定结合界面上的相互作用残基 定点突变。这一结构将作为 了解CH结构域蛋白如何与肌动蛋白细胞骨架结合。这个 第二个目的是描述纤维蛋白-波形蛋白复合体在 细胞底物黏附部位。肌动蛋白与IF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 细胞附着物。最后一个目的是确定钙蛋白的功能 通过生物化学和遗传方法的结合。在简单的 缺乏肌肉收缩系统的酵母细胞骨架--钙蛋白 应该更接近地代表它在非肌肉细胞中的功能。这个 申请人指出，对CH结构域蛋白的研究直接 与了解疾病的潜在机制有关。致癌因素 VaV的特性、强直性肌张力障碍的发病、血液紊乱和 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.