Abstract 1991: Myozap, a Novel Cardiac Protein, is a Component of the Intercalated Disc and Activates SRF-dependent Signaling
The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electrical coupling of rhythmically contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of inherited cardiac disease, in particular arrhythmogenic right ventricular cardiomyopathy involving mutations in desmoplakin, plakophilin-2, desmoglein-2, desmocollin, and plakoglobin. Given its complex structure and function we hypothesized that important constituents of the ID still remain unknown. Using a bioinformatic screen, we discovered and cloned a novel 463 amino acid/54.2 kDa cardiac protein which we termed myozap (Myocardium-enriched ZO-1-associated protein). Myozap is strongly synthesized in the heart, the protein localizes to the ID where it directly binds to and colocalizes with desmoplakin and ZO-1, two proteins implicated in the pathogenesis of human heart disease, including ARVC and heart failure. Furthermore, colocalization with plakophilin-2, β-catenin and N-cadherin could be confirmed. In a yeast-two hybrid screen for additional binding partners of myozap we identified myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity. Myozap, in turn, strongly activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a Rho-dependent fashion. Conversely, the addition of MRIP led to a significant decrease of the activation of the SRF-dependent sm22-reporter gene. These findings reveal myozap as a previously unrecognized component of a Rho-dependent signaling pathway that links the intercalated disc to cardiac gene regulation. Given its subcellular location and myriad binding partners involved in the function of the ID, myozap represents a likely mediator of cardiomyopathies.