Cypher/ZASP - a key protein in Z-disk assembly

Our laboratory has characterized a newly emerging Z-line protein complex which may directly interact with proteins localized at the cotamere: the ENH-cypher-calsarcin protein complex.
In order to examine the function of ENH, we generated both global and cardiac-specific ENH knockout mouse models. Both of these mouse models developed dilated cardiomyopathy and were associated with widening of the Z-disk. Because of the disruption of the Z-disk, we began analyzing closely associated Z-disk proteins. In wild-type muscle, we found ENH is associated with cypher and calsarcin. Notably, the short and long cypher isoforms were present in different protein complexes and are thus differentially altered upon ENH disruption.
The short cypher isoform was found to be associated with ENH and calsarcin while the long cypher isoform was found to be associated with myotilin. While the protein expression of the short cypher isoform and calsarcin was decreased in ENH-null mice, the expression of the long cypher isoform and myotilin were increased. Calsarcin interacts with filamin-C, which has been shown to interact with integrin and with both gamma and delta sarcoglycan. Thus, the ENH-cypher-calsarcin complex at the Z-line is likely to play an important role in linking the Z-line to the extracellular matrix via filamin-C. The observed up-regulation of filamin-C, members of the DGC, and integrin in ENH mutants are likely a consequence of a compensatory mechanism due to disruption of the connection between the Z-line and the extracellular matrix. Future experiments in the laboratory are designed to investigate whether ENH and cypher directly assoicate with integrin and members of the DGC.

Model of the Z-disc. Published in the Journal Trends in Cardiovascular Medicine. 2007. See the full manuscript here.

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Jongxin Mu, PhD
Lead postdoctoral scientist on the Cypher/ZASP project.


Ran Jing
Medical student on the Cypher/ZASP project.