THIN FILAMENTS AND MUSCLE REGULATION

细丝相关肌动蛋白结合蛋白具有双重功能， 控制基于肌动球蛋白的收缩和细胞骨架组装 各种肌肉和非肌肉系统。在横纹肌中， 调节蛋白复合体，肌钙蛋白-原肌球蛋白，与瘦相关 长丝，通过立体粘合和解粘来控制收缩性能 肌球蛋白与肌动蛋白的交叉桥结合反应钙/2+水平的变化。 在平滑肌中，细丝相关的钙调蛋白和降钙素可能 其功能类似于调节基于肌动球蛋白的运动和/或状态 细胞骨架组装。为了实现我们的目标，确定 这些蛋白质在横纹和横纹组织中发挥作用的调节机制 平滑的肌肉，评估它们的结构相互作用是至关重要的 分离和重组细丝及其各自的响应 与Ca/2+、肌球蛋白-交叉桥结合和磷酸化。对于更饱满的人 对灯丝的图片功能，也要了解 肌肉与相关非肌肉肌动蛋白的结构相互作用 细胞骨架蛋白最先进的电子显微镜，计算机- 将使用辅助图像分析和三维重建 确定F-肌动蛋白上细丝成分的排列 评估它们在肌动蛋白结构域中的位置和影响。重建 将被装配到F-肌动蛋白的原子图上，以详细说明与 肌动蛋白单体上的特定氨基酸簇。我们自己出版的出版物 重建和我们同事的重建证明了 这些目标。肌钙蛋白-原肌球蛋白的继续结构研究 受调控的细丝将导致分子机制的阐明 骨骼肌和心肌的松弛和激活。我们的研究 畅通肌丝将有助于理解细微 平滑肌收缩反应的调谐与血管构筑 它的细胞骨架。对分子机制的总体认识 参与调节健康肌肉组织的收缩能力 帮助我们评估疾病中出现的缺陷。对…的控制 例如，平滑肌肉的收缩能力在 血管紧张性调节和肺气道阻力，决定因素 在许多疾病过程中，如高血压和哮喘。这个 我们目标的更广泛的重要性因可能的参与而得到强调 Caldesmon、Calponin和具有共同Calponin同源结构域的蛋白质 在不同的细胞过程中，如胞质分裂、胞吐作用、皮质 细胞骨架建模和信号转导调制，即过程 它们对所有正常细胞都是必不可少的，而且在 恶毒。

Thin filament-associated actin-binding proteins have dual function, controlling actomyosin-based contractility and cytoskeletal assembly in a variety of muscle and non-muscle systems. In striated muscles, the regulatory protein complex, troponin-tropomyosin, linked to thin filaments, controls contractility by sterically blocking and unblocking myosin-crossbridge binding on actin in response to changing Ca/2+ levels. In smooth muscle, thin filament-associated caldesmon and calponin may function similarly to modulate actomyosin-based motility and/or the state of cytoskeletal assembly. To accomplish our goal to determine the regulatory mechanisms by which these proteins function in striated and smooth muscles, it is crucial to assess their structural interactions on isolated and reconstituted thin filaments and their respective responses to Ca/2+, myosin-crossbridge binding and phosphorylation. For a fuller picture of filament function, it is also essential to understand the structural interactions of muscle and related non-muscle actin- cytoskeletal proteins State of the art electron microscopy, computer- assisted image analysis and three-dimensional reconstruction will be used to determine the arrangement of thin filament components on F-actin and to evaluate their position and influence on actin domains. Reconstruction will be fitted to the atomic map of F-actin to detail contacts with specific amino acid clusters on actin monomers. Our own published reconstructions and those of our colleagues demonstrate the feasibility of these goals. Our continued structural studies on troponin-tropomyosin regulated filaments will lead to an elucidation of the molecular mechanism of relaxation and activation in skeletal and cardiac muscle. Our studies to smooth muscle filament swill contribute to understanding the fine tuning of the smooth muscle contractile response and the construction of its cytoskeleton. A general understanding of the molecular mechanisms involved in the regulation of contractility in healthy muscle tissue will aid in our evaluation of defects occurring in disease. The control of smooth muscle contractility, for example, is of great importance in the regulation of vascular tone and pulmonary airway resistance, determinants in a number of disease processes such as hypertension and asthma. The wider significance of our goals is underscore by possible participation of caldesmon, calponin and proteins with consensus calponin homology-domains in such diverse cellular processes as cytokinesis, exocytosis, cortical cytoskeleton modeling and signal transduction modulation, i.e. processes that are essential to all normal cells and that can become aberrant in malignancy.