Sheikh Farah, Bang Marie-Louise, Lange Stephan, Chen Ju
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Trends Cardiovasc Med. 2007 Nov;17(8):258-62. doi: 10.1016/j.tcm.2007.09.002.
The striated muscle Z line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human muscle disease. Cypher/Z-band alternatively spliced PDZ-motif protein, a PDZ-LIM protein in the Z line, binds to alpha-actinin (via its PDZ domain) and has been suggested to function as a linker-strut to maintain cytoskeletal structural integrity during contraction. Cypher may also participate in signaling pathways by binding to protein kinase C via its LIM domains. Analysis of Cypher-deficient mice has revealed that Cypher plays an integral role in Z-line maintenance/integrity of striated muscles and the pathogenesis of congenital myopathies, including cardiomyopathy. These studies have led to the subsequent discovery of Cypher mutations in human patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, as well as skeletal muscle myopathies, which have been recently termed zaspopathies. The recent discovery of various alternatively spliced isoforms of Cypher with potentially distinct structural and signaling roles brings a different level of complexity to the mechanisms underlying Cypher-based human myopathies. This review will focus on recent developments on the role of Cypher and its isoforms in striated muscle structure, signaling, and disease to provide insights into the mechanisms involved in the pathogenesis of Z-line-associated human myopathies.
横纹肌Z线是肌节之间边界处的一种多蛋白复合体，在维持横纹肌结构和功能方面发挥着不可或缺的作用。多种与Z线相关的蛋白已被鉴定出来，并显示在人类肌肉疾病的发病机制中发挥着越来越重要的作用。Cypher/Z带可变剪接PDZ基序蛋白是Z线中的一种PDZ-LIM蛋白，它（通过其PDZ结构域）与α-辅肌动蛋白结合，并被认为在收缩过程中作为连接支柱发挥作用，以维持细胞骨架结构的完整性。Cypher还可能通过其LIM结构域与蛋白激酶C结合而参与信号通路。对缺乏Cypher的小鼠的分析表明，Cypher在横纹肌的Z线维持/完整性以及包括心肌病在内的先天性肌病的发病机制中发挥着不可或缺的作用。这些研究随后导致在患有扩张型心肌病、肥厚型心肌病以及骨骼肌肌病的人类患者中发现了Cypher突变，这些疾病最近被称为zaspopathies。最近发现的具有潜在不同结构和信号作用的Cypher的各种可变剪接异构体，为基于Cypher的人类肌病的潜在机制带来了不同程度的复杂性。本综述将聚焦于Cypher及其异构体在横纹肌结构、信号传导和疾病中的作用的最新进展，以深入了解与Z线相关的人类肌病发病机制中涉及的机制。
