TROPONIN T AND THE REGULATION OF CONTRACTION

描述（应用摘要）：“肌钙蛋白T（TnT）是三种 形成肌钙蛋白复合物（Tn）的蛋白质（包括TnI和TnC）， 调节骨骼肌收缩 序列分析 TnT基因预测多达64种不同的亚型，由于存在 在N-末端的5个选择性剪接外显子和2个相互剪接外显子中， 在C位的排他性选择性剪接外显子（α和β） 终点站 以前的研究表明，TnT在 收缩的调节是与复合物相互作用并锚在复合物上， TnI和TnC通过TnT与肌动蛋白的相互作用， 原肌球蛋白（Tm）。 我们实验室最近的两项结果表明， 除了这一作用，TnT还关键地参与调节 肌动球蛋白ATP酶激活。首先，TnT的C-末端（含有 α或β）与TnC相互作用，这种相互作用似乎是 激活肌动球蛋白ATP酶活性所必需的。 这 相互作用部分地决定了收缩的Ca 2+敏感性， 其取决于是否存在α或β而不同。二是 TnT的N-末端区域（含有各种可变剪接的 外显子）似乎决定肌动球蛋白ATP酶的激活水平 一旦这种与TnC的相互作用发生。 我们最近的观察 提示TnT的两个选择性剪接区（N-和C-）在 肌动球蛋白ATP酶激活的调节。 主要的问题是 该提案中涉及的问题是：TnT的结构变化， 在这两个区域的选择性剪接赋予，影响这一点 TnT的新功能？ 我们的工作假设，将在 目前认为，Ca ~（2+）与TnC结合引起相互作用 在TnC和TnT的C-末端之间（含有α或β），和 引起ATP酶活性的激活。 Ca 2+敏感性 这种激活依赖于α/β剪接变体和 最大激活水平由特定的N-末端决定 存在的TnT变体。"

DESCRIPTION (application abstract): "Troponin T (TnT) is one of three proteins (including TnI and TnC) that form the troponin complex (Tn), which regulates skeletal muscle contraction. Sequence analysis of the TnT gene predicts as many as 64 different isoforms, due to the presence of 5 alternatively spliced exons at the N-terminus and 2 mutually exclusive alternatively spliced exons (alpha and beta) at the C- terminus. Previous studies have suggested that the role of TnT in the regulation of contraction is to interact with and anchor the complex of TnI and TnC to actin-containing filaments through TnT's interaction with tropomyosin (Tm). Two recent results from our lab suggest that, in addition to this role, TnT is critically involved in the regulation of actomyosin ATPase activation. First, the C-terminus of TnT (containing alpha or beta) interacts with TnC, and this interaction seems to be required for the activation of actomyosin ATPase activity. This interaction in part determines the Ca2+ -sensitivity of contraction, which differs depending on whether alpha or beta is present. Second, the N-terminal region of TnT (containing various alternatively spliced exons) appears to determine the level of activation of actomyosin ATPase activity once this interaction with TnC occurs. Our recent observations implicate both alternatively spliced regions (N- and C-) of TnT in the regulation of actomyosin ATPase activation. The major question being addressed in this proposal is: how do structural changes in TnT, conferred by alternative splicing in these two regions, affect this novel function of TnT? Our working hypothesis, which will be tested in the present proposal, is that Ca2+ binding to TnC causes an interaction between TnC and the C-terminus of TnT (containing alpha or beta) and causes an activation of the ATPase activity. The Ca2+ -sensitivity of this activation depends on the alpha/beta splice variants and the maximum level of activation is determined by the particular N-terminal TnT variant which is present."