ALP/Enigma PDZ-LIM domain proteins in the heart

Abstract

Actinin-associated LIM protein (ALP) and Enigma are two subfamilies of Postsynaptic density 95, discs large and zonula occludens-1 (PDZ)-Lin-11, Isl1 and Mec-3 (LIM) domain containing proteins. ALP family members have one PDZ and one LIM domain, whereas Enigma proteins contain one PDZ and three LIM domains. Four ALP and three Enigma proteins have been identified in mammals, each having multiple splice variants and unique expression patterns. Functionally, these proteins bind through their PDZ domains to alpha-actinin and bind through their LIM domains or other internal protein interaction domains to other proteins, including signaling molecules. ALP and Enigma proteins have been implicated in cardiac and skeletal muscle structure, function and disease, neuronal function, bipolar disorder, tumor growth, platelet and epithelial cell motility and bone formation. This review will focus on recent advances in the biological roles of ALP/Enigma PDZ-LIM domain proteins in cardiac muscle and provide insights into mechanisms by which mutations in these proteins are related to human cardiac disease.

Figure 1

Characterization of ALP/Enigma protein family in invertebrates (A and B) and vertebrate (C and D). (A) The C. elegans T11B7.4 gene encodes four splice isoforms. T11B7.4a is similar to ALP family proteins in vertebrate containing one PDZ and one LIM domain. T11B7.4b and d are similar to Enigma family proteins in vertebrate containing one PDZ and four LIM domains. T11B7.4c does not have the PDZ domain. (B) The Drosophila homolog of human ZASP has six identified splice isoforms. (C) In vertebrate, there are four genes (ALP, CLP36, Mystique and RIL) which encode ALP family proteins, and multiple splice isoforms. (D) In vertebrate, there are three genes (Enigma, ENH and Cypher/ZASP) for Enigma subfamily with multiple splice isoforms. ZM is a conserved motif in Cypher/ZASP, ALP, CLP36 and Drosophila ZASP. ZM motif interacts with the rod-region of α-actinin-2. AM is a conserved motif in ALP subfamily. AM contains a potential PKC phosphorylation site.