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Figure 2. Evolution of the Popdc gene family(A) Animal phyla for which genomic sequences encoding Popdc proteins are present in the NCBI or Ensembl databases are boxed in red. (B) Phylogenetic dendrogram of Popdc protein sequences. Vertebrate Popdc proteins cluster in two groups: Popdc1 and Popdc2/3. Proteins found in basic chordates (Ciona) also distribute in these two subfamilies, whereas Popdc proteins of protostomes (Drosophila, Aplysia and Capitaella) form an independent subgroup equally distant from Popdc1 and Popdc2/3 subgroups. Significantly, however, the cnidarian (Clytia) Popdc protein appears to be orthologous to Popdc1, suggesting that Popdc1 represent the ancestral form of the protein family. (C) Protein sequence alignment of the PBC of Popdc proteins. Despite 650–850 million years of evolutionary distance between cnidarians and vertebrates, two sequence elements (FL/IDSPEW/F and FQVT/SL/I) are strongly conserved. (D) 3D model of the Popeye domain of human POPDC1. Similar to other cAMP-binding domains, the roof of the Popeye domain consists of a number β-strands, whereas the lid is α-helical and positions itself over the PBC in response to cyclic nucleotide binding and shields the ligand from solvent [36]. The residues of the PBC are depicted as yellow halos surrounding the cAMP molecule. The Cav3-binding site is also demarcated and located at the distal end of the lid domain. At this position, the binding site is likely to experience significant conformational changes in response to ligand binding. (E) Comparison of the consensus sequence of the PBC of Popdc proteins and the consensus sequence of cNMP-binding sites, which are aligned in PROSITE (http://prosite.expasy.org/PS00889). Note that the two consensus sequences do not resemble each other. In both cases, however, two stretches of conserved sequence motifs border a sequence of weak conservation. Amino acids labelled by a star in the Popdc sequence have been mutagenized and shown to be essential for cAMP binding [6]. Image published in: Brand T et al. (2014) © 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY)(http://creativecommons. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution license Larger Image Printer Friendly View

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