Cypher/ZASP is a novel A-kinase anchoring protein.

Changsong Lin, Xiaogang Guo, Stephan Lange, Jie Liu, Kunfu Ouyang, Xiang Yin, Liujun Jiang, Yibo Cai, Yongxin Mu, Farah Sheikh, Sheng Ye, Ju Chen, Yuehai Ke, Hongqiang Cheng

The Journal of biological chemistry 2013 Oct 11

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PKA signaling is important for the post-translational modification of proteins, especially those in cardiomyocytes involved in cardiac excitation-contraction coupling. PKA activity is spatially and temporally regulated through compartmentalization by protein kinase A anchoring proteins. Cypher/ZASP, a member of PDZ-LIM domain protein family, is a cytoskeletal protein that forms multiprotein complexes at sarcomeric Z-lines. It has been demonstrated that Cypher/ZASP plays a pivotal structural role in the structural integrity of sarcomeres, and several of its mutations are associated with myopathies including dilated cardiomyopathy. Here we show that Cypher/ZASP, interacting specifically with the type II regulatory subunit RIIα of PKA, acted as a typical protein kinase A anchoring protein in cardiomyocytes. In addition, we show that Cypher/ZASP itself was phosphorylated at Ser(265) and Ser(296) by PKA. Furthermore, the PDZ domain of Cypher/ZASP interacted with the L-type calcium channel through its C-terminal PDZ binding motif. Expression of Cypher/ZASP facilitated PKA-mediated phosphorylation of the L-type calcium channel in vitro. Additionally, the phosphorylation of the L-type calcium channel at Ser(1928) induced by isoproterenol was impaired in neonatal Cypher/ZASP-null cardiomyocytes. Moreover, Cypher/ZASP interacted with the Ser/Thr phosphatase calcineurin, which is a phosphatase for the L-type calcium channel. Taken together, our data strongly suggest that Cypher/ZASP not only plays a structural role for the sarcomeric integrity, but is also an important sarcomeric signaling scaffold in regulating the phosphorylation of channels or contractile proteins.

Citation

Changsong Lin, Xiaogang Guo, Stephan Lange, Jie Liu, Kunfu Ouyang, Xiang Yin, Liujun Jiang, Yibo Cai, Yongxin Mu, Farah Sheikh, Sheng Ye, Ju Chen, Yuehai Ke, Hongqiang Cheng. Cypher/ZASP is a novel A-kinase anchoring protein. The Journal of biological chemistry. 2013 Oct 11;288(41):29403-13