“Z”eroing in on the Role of Cypher in Striated Muscle Function, Signaling, and Human Disease

Abstract

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/ZASP, a PDZ-LIM protein in the Z-line, binds to α-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 (PKC) 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.

Zasp regulates integrin activation

“…Zasp is mutated in cardiomyopathies and myofibrillar myopathies and knockout of Zasp in mice, zebrafish or Drosophila leads to severe muscle defects (Jani and Schöck, 2007;Sheikh et al, 2007;van der Meer et al, 2006;Zhou et al, 2001). The ability of muscles to transmit intracellular actomyosin-mediated contractility to neighboring cells and tissues requires adhesion to the ECM and assembly of cytoskeletal complexes that link adhesion receptors to the contractile apparatus (Sparrow and Schöck, 2009).…”

“…While Zasp lacks enzymatic activity, it can act as an adaptor protein, binding a-actinin-2 to stabilize Z-lines in striated and cardiac muscle (Faulkner et al, 1999;Zhou et al, 2001;Zhou et al, 1999). Mutated Zasp can lead to the development of hypertrophic cardiomyopathies and myofibrillar myopathies (Sheikh et al, 2007). Mammalian Zasp is subject to extensive alternative splicing with up to six protein variants expressed, but all mammalian Zasp isoforms are composed of an N-terminal PDZ domain followed by a Zasp-like motif (ZM), an intervening sequence of variable length and no, one or three C-terminal LIM domains (Fig.…”

The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse

“…The Z-line is a multiprotein complex, which defines the boundaries between sarcomeres and plays a pivotal role in skeletal muscle structure and function, including sarcomere assembly and organization, muscle force generation and transmission, mechanosensing, signaling and sarcolemmal membrane integrity (reviewed by Frank et al, 2006;Luther, 2009;Sheikh et al, 2007). Within the Z-line, nebulin C-terminal modules interact with the intermediate filament desmin Tonino et al, 2010) as well as the actin barbed-end capping protein CapZ (Pappas et al, 2008).…”

Nebulin, a multi-functional giant

“…Nebulin's C terminus is located within the highly specialized boundary of the sarcomere (Z-disc), and plays an important role in myofibril assembly, mechanosensing, signaling, force generation and transmission, and sarcolemmal resilience (reviewed by Clark et al, 2002;Frank et al, 2006;Luther, 2009;Sheikh et al, 2007;Fig. 1).…”