Myosin light chain kinase and the role of myosin light chain phosphorylation in skeletal muscle.
Myosin light chain kinase and the role of myosin light chain phosphorylation in skeletal muscle.
复制标题
肌球蛋白轻链激酶和肌球蛋白轻链磷酸化在骨骼肌中的作用。
DOI：
10.1016/j.abb.2011.01.017
复制
发表时间：
2011-06-15
影响因子：
3.9
通讯作者：
Vandenboom R
中科院分区：
文献类型：
--
作者：
Stull JT;Kamm KE;Vandenboom R
骨骼肌肌球蛋白轻链激酶（skMLCK）是一种钙/钙调蛋白依赖性丝氨酸-苏氨酸蛋白激酶，可磷酸化肌节肌球蛋白的调节轻链（RLC）。它由MYLK 2基因表达，特异性地在骨骼肌纤维中表达，在快速收缩的肌肉中最丰富。在生物化学上，激活发生时，Ca 2+与钙调蛋白结合形成（Ca 2+）4·钙调蛋白复合物，足以通过扩散限制、化学计量结合和从skMLCK催化核心置换调节片段来激活。然后RLC的N-末端序列延伸通过暴露的催化裂缝用于Ser 15磷酸化。Ca 2+的去除导致钙调素的缓慢解离和skMLCK的失活。组合的生物化学性质为RLC磷酸化的生理响应提供了独特的特征，包括（1）通过Ca 2 +/钙调蛋白快速激活MLCK，（2）限制激酶活性，因此磷酸化比收缩慢，（3）松弛后MLCK失活缓慢，以及（4）相对于肌球蛋白轻链磷酸酶（MLCP），激酶活性大得多。肌球蛋白RLC的SkMLCK磷酸化调节脊椎动物骨骼肌功能的机械方面。在透化骨骼肌纤维中，肌球蛋白结构的磷酸化介导的改变增加了肌球蛋白跨桥产生力的速率，从而增加了收缩装置的Ca 2+敏感性。刺激诱导的RLC磷酸化在完整的肌肉中的增加产生等长和同心力增强，以增强肌肉工作的动态方面和在未疲劳或疲劳的肌肉中的功率。此外，RLC磷酸化介导的增强可能与人类骨骼肌激活的神经策略相互作用，以改善中枢或外周疲劳。
Skeletal muscle myosin light chain kinase (skMLCK) is a dedicated Ca2+/calmodulin-dependent serine-threonine protein kinase that phosphorylates the regulatory light chain (RLC) of sarcomeric myosin. It is expressed from the MYLK2 gene specifically in skeletal muscle fibers with most abundance in fast contracting muscles. Biochemically, activation occurs with Ca2+ binding to calmodulin forming a (Ca2+)4•calmodulin complex sufficient for activation with a diffusion limited, stoichiometic binding and displacement of a regulatory segment from skMLCK catalytic core. The N-terminal sequence of RLC then extends through the exposed catalytic cleft for Ser15 phosphorylation. Removal of Ca2+ results in the slow dissociation of calmodulin and inactivation of skMLCK. Combined biochemical properties provide unique features for the physiological responsiveness of RLC phosphorylation, including (1) rapid activation of MLCK by Ca2+/calmodulin, (2) limiting kinase activity so phosphorylation is slower than contraction, (3) slow MLCK inactivation after relaxation and (4) much greater kinase activity relative to myosin light chain phosphatase (MLCP). SkMLCK phosphorylation of myosin RLC modulates mechanical aspects of vertebrate skeletal muscle function. In permeabilized skeletal muscle fibers, phosphorylation-mediated alterations in myosin structure increase the rate of force-generation by myosin cross bridges to increase Ca2+-sensitivity of the contractile apparatus. Stimulation-induced increases in RLC phosphorylation in intact muscle produces isometric and concentric force potentiation to enhance dynamic aspects of muscle work and power in unfatigued or fatigued muscle. Moreover, RLC phosphorylation-mediated enhancements may interact with neural strategies for human skeletal muscle activation to ameliorate either central or peripheral aspects of fatigue.