Regulation of actin dynamics during myofibril assembly

项目摘要 横纹肌的肌节是构成肌肉收缩器官的基本单位。装配和维持 有组织的肌节结构对于肌肉的适当收缩和松弛是必需的。肌动蛋白是一种 肌节细丝的主要成分，以及细丝的长度和取向， 在横纹肌中调节。然而，肌节肌动蛋白的组装和维持机制 细丝是复杂的，人们对其了解甚少。已经鉴定了许多肌动蛋白动力学的调节剂， 骨骼肌，其中一些与遗传性肌肉疾病有关。线状体肌病涉及 在骨骼肌中形成异常的富含肌动蛋白的聚集体或杆，由肌动蛋白突变引起，或 肌动蛋白动力学的调节者。因此，肌动蛋白动力学的调节对于构建 骨骼肌中的功能性收缩装置，该系统的功能障碍导致肌肉疾病。 为了研究横纹肌肌动蛋白动力学的调节机制，我们使用线虫 秀丽隐杆线虫作为模型系统。C. elegans是横纹肌，大多数 肌节蛋白在C. elegans优雅and humans人类. In C.我们已经发现， ADF/cofilin（ADF-60 B）、AIP 1（ADF-78和AIPL-1）和环化酶相关蛋白（CAS-1）可增强周转 是肌动蛋白丝的重要组成部分，也是肌节肌动蛋白丝有组织组装的必要条件。此外，我们还发现， β-13作为一种新的肌肉肌动蛋白调节剂。此外，我们获得的证据表明， 肌节肌动蛋白丝与C.肌肉 该项目的中心假设是，肌动蛋白丝动力学的适当位点特异性调节是 是肌节肌动蛋白丝组装和维持所必需的。我们提出三个目标：（目标1） 确定ADF/cofilin、AIP 1和β-13如何调节肌节肌动蛋白组装，（目的2）以确定 环化酶相关蛋白如何调节肌动蛋白丝的动力学，以及（目的3）确定如何 肌节肌动蛋白丝锚定在它们的倒刺末端附近。我们希望这项研究的结果将 为横纹肌肌动蛋白动力学的调节提供了新的见解。大多数肌动蛋白调节 在这个项目中研究的蛋白质也在哺乳动物骨骼肌中表达，其中一些蛋白质是 与人类遗传性肌肉疾病有关我们希望我们对模式生物的研究将有助于 了解正常和病理条件下肌原纤维组装和维持的保守机制 条件

Project Summary Sarcomere in striated muscle is the basic unit of contractile apparatuses. Assembly and maintenance of organized sarcomeric structures are essential for proper contraction and relaxation in muscle. Actin is one of the major components of sarcomeric thin filaments, and length and orientation of the filaments are precisely regulated in striated muscle. However, the mechanism of assembly and maintenance of sarcomeric actin filaments is complex and poorly understood. A number of regulators of actin dynamics have been identified in skeletal muscle, and some of them are linked to genetic muscle disorders. Nemaline myopathy involves formation of abnormal actin-rich aggregates or rods in skeletal muscle and is caused by mutations in actin or regulators of actin dynamics. Therefore, the regulation of actin dynamics is fundamentally important for building functional contractile apparatuses in skeletal muscle, and malfunction in this system leads to muscle disorders. To investigate the regulatory mechanism of actin dynamics in striated muscle, we use the nematode Caenorhabditis elegans as a model system. Body wall muscle of C. elegans is striated muscle, and most of sarcomeric proteins are conserved between C. elegans and humans. In C. elegans, we have identified that ADF/cofilin (UNC-60B), AIP1 (UNC-78 and AIPL-1), and cyclase-associated protein (CAS-1) enhance turnover of actin filaments and essential for organized assembly of sarcomeric actin filaments. In addition, we identified SUP-13 as a new regulator of muscle actin. Furthermore, we obtained evidence that the barbed ends of sarcomeric actin filaments are aligned to previously unrecognized Z-line-like structures in C. elegans muscle. The central hypothesis of this project is that proper site-specific regulation of actin filament dynamics is required for assembly and maintenance of sarcomeric actin filaments. We propose three aims: (Aim 1) to determine how sarcomeric actin assembly is regulated by ADF/cofilin, AIP1, and SUP-13, (Aim 2) to determine how actin filament dynamics are regulated by cyclase-associated protein, and (Aim 3) to determine how sarcomeric actin filaments are anchored near their barbed ends. We expect that results of this research will provide new insight into the regulation of actin dynamics in striated muscle. Most of the actin-regulatory proteins studied in this project are also expressed in mammalian skeletal muscle, and some of them are involved in genetic muscle disorders in humans. We hope that our research in a model organism will help to understand the conserved mechanism of myofibril assembly and maintenance under normal and pathological conditions.