Abstract
The PDZ and LIM domain-containing protein family is encoded by a diverse group of genes whose phylogeny has currently not been analyzed. In mammals, ten genes are found that encode both a PDZ- and one or several LIM-domains. These genes are: ALP, RIL, Elfin (CLP36), Mystique, Enigma (LMP-1), Enigma homologue (ENH), ZASP (Cypher, Oracle), LMO7 and the two LIM domain kinases (LIMK1 and LIMK2). As conventional alignment and phylogenetic procedures of full-length sequences fell short of elucidating the evolutionary history of these genes, we started to analyze the PDZ and LIM domain sequences themselves. Using information from most sequenced eukaryotic lineages, our phylogenetic analysis is based on full-length cDNA-, EST-derived- and genomic- PDZ and LIM domain sequences of over 25 species, ranging from yeast to humans. Plant and protozoan homologs were not found. Our phylogenetic analysis identifies a number of domain duplication and rearrangement events, and shows a single convergent event during evolution of the PDZ/LIM family. Further, we describe the separation of the ALP and Enigma subfamilies in lower vertebrates and identify a novel consensus motif, which we call ‘ALP-like motif’ (AM). This motif is highly-conserved between ALP subfamily proteins of diverse organisms. We used here a combinatorial approach to define the relation of the PDZ and LIM domain encoding genes and to reconstruct their phylogeny. This analysis allowed us to classify the PDZ/LIM family and to suggest a meaningful model for the molecular evolution of the diverse gene architectures found in this multi-domain family.
Highlights
The sequencing and annotation of an increasing number of genomes has led to a huge amount of protein sequence data
The ZASP-like motif (ZM) motif has been described to function in concert with the PDZ domain to localize ZASP to aactinin, the major Z-disk cross linker in sarcomers [28,49]
We show alignments for both motifs, it is important to note that we have newly discovered the ALP-like motif and denoted it AM in analogy to the earlier denoted ZASP-like motif (ZM), but no structural or functional similarity is apparent between both motifs
Summary
The sequencing and annotation of an increasing number of genomes has led to a huge amount of protein sequence data. The classification of protein families is based on homologous relationships and several methods are currently available for clustering proteins into families [2,3]. Most of those approaches rely on sequence similarity measures, such as those obtained with BLAST [4] or hidden Markov models [5]. Because many proteins contain multiple domains, many of these methods of protein clustering result in the establishment of incorrect families. This problem is complicated in metazoan proteomes, and the human proteome in particular, where multi-domain proteins are abundant
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