A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo
A Single Serine in the Carboxyl Terminus of Cardiac Essential Myosin Light Chain-1 Controls Cardiomyocyte Contractility In Vivo
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DOI：
10.1161/circresaha.108.186676
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发表时间：
2009-03-13
影响因子：
20.1
通讯作者：
Rottbauer, Wolfgang
中科院分区：
文献类型：
--
作者：
Meder, Benjamin;Laufer, Christina;Rottbauer, Wolfgang
虽然众所周知，心脏必需肌球蛋白轻链-1（cmlc-1）基因突变可导致肥厚型心肌病，但对cMLC-1在心脏中的确切体内结构和功能作用知之甚少。我们已经分离出了斑马鱼的突变体懒苏珊（laz），它显示出两个心室的收缩力严重降低。通过定位克隆，我们确定了斑马鱼cmlc-1基因内的一个无义突变负责的拉兹表型，导致羧基末端截短的cMLC-1的表达。尽管cMLC-1的完全丧失导致可归因于受损的心脏肌角化的心脏收缩性，但在laz突变心脏中羧基末端截短的cMLC-1的表达足以用于正常的心脏肌角化，但以细胞自主的方式严重损害心脏收缩性。野生型cMLC-1的过表达恢复了laz突变型心肌细胞的收缩性，而磷酸化位点丝氨酸195缺陷型cMLC-1（cMLC-1 S195 A）的过表达不能重建laz突变型心肌细胞的心脏收缩性。相比之下，在位置195（cMLC-1（S195 D））上引入拟磷酸化氨基酸拯救心肌细胞收缩性，首次证明了cMLC-1的羧基末端尤其是丝氨酸195在调节心肌收缩性中的重要作用。(Circ Res. 2009; 104：650-659）。
Although it is well known that mutations in the cardiac essential myosin light chain-1 (cmlc-1) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant lazy susan (laz), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish cmlc-1 gene to be responsible for the laz phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1. Whereas complete loss of cMLC-1 leads to cardiac acontractility attributable to impaired cardiac sarcomerogenesis, expression of a carboxyl-terminally truncated cMLC-1 in laz mutant hearts is sufficient for normal cardiac sarcomerogenesis but severely impairs cardiac contractility in a cell-autonomous fashion. Whereas overexpression of wild-type cMLC-1 restores contractility of laz mutant cardiomyocytes, overexpression of phosphorylation site serine 195-deficient cMLC-1 (cMLC-1S195A) does not reconstitute cardiac contractility in laz mutant cardiomyocytes. By contrast, introduction of a phosphomimetic amino acid on position 195 (cMLC-1(S195D)) rescues cardiomyocyte contractility, demonstrating for the first time an essential role of the carboxyl terminus and especially of serine 195 of cMLC-1 in the regulation of cardiac contractility. (Circ Res. 2009; 104: 650-659.)