STRUCTURAL CHANGES IN SIGNALING IN CALCIUM REGULATIONS

描述（改编自申请人摘要）： 建议的研究是了解钙依赖的分子基础， 调节生物化学活性。 实验方法是利用 钙调素与骨骼肌和平滑肌肌球蛋白轻链的相互作用 激酶（MLCK）的酶活性的截断突变体。 的 申请人将研究底物和ATP如何调节这些 相互作用，并寻找2Ca 2+·CaM·MLCK中间体的证据 失活的复合物。 申请人将调查 平滑肌MLCK催化核心N端纤连蛋白结构域 与催化核心，以及它如何可能是由钙调素结合， MLCK。 CaM与磷酸化酶激酶（PhK）的相互作用，利用CaM结合 来自催化亚基PhK（302-306）的肽。 钙调素与平滑肌蛋白钙调素（CaD）的相互作用， 来自CaD序列的CaM结合肽。 在骨骼肌和心脏形式中的TnC/TnI相互作用， 强调改进当前的骨骼相互作用模型， 理解功能差异的结构基础， 心脏系统 申请人还将这些研究扩展到三元 使用心脏系统的TnC/TnI/TnT复合物。 生化调节是健康功能的关键。 监管细分 如果机制未得到纠正，通常会导致病理状况， 不受控制的增殖或细胞死亡。 了解潜在的 因此，调节的分子机制在以下方面具有根本的重要性： 健康研究。

DESCRIPTION (Adapted from applicant's abstract): The objective of the proposed research is to understand the molecular basis for Ca2+-dependent regulation of biochemical activity. The experimental approach is to utilize CaM's interactions with both skeletal and smooth muscle myosin light chain kinase (MLCK) utilizing enzymatically active truncation mutants. The applicant will investigate how substrate and ATP modulate these interactions, and look for evidence of a 2Ca2+.CaM.MLCK intermediate inactivated complex. The applicant will investigate the interaction of the fibronectin domain N-terminal to the catalytic core in smooth muscle MLCK with the catalytic core and how it might be modulated by CaM binding to MLCK. CaM's interaction with phosphorylase kinase (PhK), utilizing CaM-binding peptides from the catalytic subunit PhK(302-306). CaM's interaction with the smooth muscle protein caldesmon (CaD) utilizing CaM-binding peptides from the CaD sequence. TnC/TnI interactions in both skeletal muscle and cardiac forms, with an emphasis on improving the current model for skeletal interactions and understanding the structural basis for the differences in function with the cardiac system. The applicant will also expand these studies to the ternary TnC/TnI/TnT complex using the cardiac system. Biochemical regulation is key to healthy function. Breakdown of regulatory mechanisms if uncorrected generally leads to pathological conditions and to uncontrolled proliferation or cell death. Understanding the underlying molecular mechanisms of regulation is thus of fundamental importance in health research.