Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy
Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy
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DOI：
10.1007/s00018-012-1142-y
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发表时间：
2013-02-01
影响因子：
8
通讯作者：
Noegel, Angelika A.
中科院分区：
文献类型：
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作者：
Peche, Vivek S.;Holak, Tad A.;Noegel, Angelika A.
环化酶相关蛋白是高度保守的蛋白，在肌动蛋白动力学的调节中发挥作用。高等真核生物有两种亚型，即CAP1和CAP2。为了研究CAP2的体内功能，我们用基因陷阱的方法产生了CAP2基因失活的小鼠。突变的小鼠体重减轻，存活率下降。此外，他们还出现了严重的心脏缺陷，表现为扩张型心肌病(DCM)，与基础心率急剧减慢以及房室传导时间延长有关。此外，CAP2缺乏的肌原纤维表现出钙调控力发展的协同性降低。在显微镜下，我们观察到随着纤维化的发展，肌节呈散乱排列。我们分析了CAP2的S在肌动蛋白组装中的作用，发现它隔离G-肌动蛋白并有效地碎裂细丝。这个活动完全驻留在它的WASP同源域中。因此，CAP2是心肌肌节的重要组成部分，对心脏系统的生理功能是必不可少的，而CAP2的缺失会导致DCM和各种心脏缺陷。
Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calcium-regulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects.