Enigma in cardiac hypertrophy.

The Enigma subfamily belongs to the PDZ(for PSD-95, DLG, ZO-1) and LIM(for LIN-11, Isl-1, MEC-3) encoding protein family. This family is composed of at least four different members: Enigma (also called PD-LIM7; LMP-1), Enigma homologue (ENH), ZASP/Cypher/ Oracle, and LMP-4. All members of the PDZ–LIM Enigma family, including ENH, are cytoplasmic proteins that bind to the cytoskeleton through a direct interaction between their PDZ domain and a-actinin, thus localizing the protein to the Z-disk of cardiac myocytes. The LIM domain is a cysteine-rich domain, composed of two independent zinc-coordinated fingers, that has been proposed to participate in protein–protein interactions. ENH1 was first identified as an adaptor for protein kinase C (PKC) by using a yeast two-hybrid system. PKC binds to any of the three LIM domains of ENH1 in an isoform-specific manner. In neurons, ENH1 recruits PKC1 to the N-type voltage-gated Ca2+ channel. The LIM2 motif of ENH1 has also been shown to bind protein kinase D1 (PKD1) to regulate the activity of the a1c subunit of the L-type voltage-gated Ca2+ channel. Interestingly, four spliced variants of the enh gene have been described, namely ENH1, -2, -3, and -4. –3 Only ENH1 contains the LIM domains (see Figure 1 in Yamazaki et al.) and, therefore, should be able to regulate protein kinases and Ca2+ channel activities. Yamazaki et al. demonstrate that ENH1 is expressed in the embryonic and neonatal heart but not in the adult, where it is replaced by ENH3 and ENH4. As shown for many other proteins, a shift