Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany.
Cell Mol Life Sci. 2013 Feb;70(3):527-43. doi: 10.1007/s00018-012-1142-y. Epub 2012 Sep 4.
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.
肌球蛋白关联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同工型，CAP1 和 CAP2。为了研究 CAP2 的体内功能，我们利用基因捕获方法使 CAP2 基因失活，从而产生了突变小鼠。突变小鼠的体重下降，存活率降低。此外，它们还出现了严重的心脏缺陷，表现为扩张型心肌病（DCM），伴有基础心率明显降低和心房及心室传导时间延长。此外，CAP2 缺陷肌原纤维的钙调节力发展的协作性降低。在微观水平上，我们观察到肌节排列紊乱伴纤维化的形成。我们分析了 CAP2 在肌动蛋白组装中的作用，发现它可以隔离 G-肌动蛋白并有效地使纤维丝片段化。这种活性完全存在于其 WASP 同源结构域中。因此，CAP2 是心肌肌节的重要组成部分，对于心脏系统的生理功能至关重要，其缺乏会导致 DCM 和各种心脏缺陷。
