Prevalence and diversity of Ly6/uPAR proteins and three-finger LU domains from the analysis of invertebrate genomes

The family of Three-Finger Proteins (TFPs or Ly6/uPAR) containing three-finger domains (LU domains) with a characteristic three-finger fold was initially characterized for toxins from the venom of snakes of the family Elapidae. TFPs have been described in vertebrates and some invertebrates, where they are known to participate in the regulation of membrane receptors, intercellular recognition, signal transduction, embryogenesis, and the functioning of the nervous, immune, and reproductive systems. Although a vast amount of genomic information has recently become available, the diversity and representation of TFPs in various groups of organisms, as well as the evolution of proteins belonging to this family, remain poorly understood. In this study, we employed the bioinformatics methods to analyze the annotated genomes of various metazoans available in open databases. Protein sequence analysis using hidden Markov models enabled the identification of TFPs in the genomes of the members of all the metazoan phyla, including those most evolutionarily distant from humans: ctenophores (Ctenophora), sponges (Porifera), placozoans (Placozoa), and cnidarians (Cnidaria). Further domain annotation revealed the presence of proteins with three-finger domains and a previously undescribed domain architecture in cnidarians, mollusks, and arthropods. Comparison of the LU domains of early metazoans to those of humans revealed a high degree of sequence similarity (up to 69%) for some proteins. For example, the LU domains of the human activin receptors ACVR and the GPI-anchored proteins Ly6D and Lynx2 (Lypd1) appeared conserved. The function and mechanisms of action of invertebrate TFPs remain unknown. An analysis of the annotated genomes of some fungi and plants and two published genomes of choanoflagellates (Choanoflagellata), a phylum of unicellular organisms that are the most phylogenetically close to the Metazoa, revealed no presence of sequences encoding TFPs. It is hypothesized that TFPs first appeared during the evolution of protozoa, upon the transition of animals to multicellularity.