Biochem Soc Trans
April 1, 2014;
The cAMP-binding Popdc proteins have a redundant function in the heart.
Popdc (Popeye-domain-containing) genes encode membrane-bound proteins and are abundantly present in cardiac myocytes
and in skeletal muscle
fibres. Functional analysis of Popdc1
) and Popdc2
in mice and of popdc2
in zebrafish revealed an overlapping role for proper electrical conduction in the heart
and maintaining structural integrity of skeletal muscle
. Popdc proteins mediate cAMP signalling and modulate the biological activity of interacting proteins. The two-pore channel TREK-1
interacts with all three Popdc proteins. In Xenopus oocytes, the presence of Popdc proteins causes an enhanced membrane transport leading to an increase in TREK-1
current, which is blocked when cAMP levels are increased. Another important Popdc-interacting protein is caveolin 3, and the loss of Popdc1
affects caveolar size. Thus a family of membrane-bound cAMP-binding proteins has been identified, which modulate the subcellular localization of effector proteins involved in organizing signalling complexes and assuring proper membrane physiology of cardiac myocytes
Biochem Soc Trans
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Figure 1. Model of Popdc proteins and expression of Popdc1 in the heart(A) Working model of Popdc proteins. The Popdc protein is found as a dimer in cells and consists of a short extracellular domain, which is subject to glycosylation, three transmembrane domains and a conserved Popeye domain in the intracellular part of the protein. The C-terminus is variable in length and subject to alternative splicing. aa, amino acids. (B–E) Immunohistochemical detection of Popdc1 in the adult mouse heart. Sections were counterstained with DAPI to label the nuclei. (B) Expression of Popdc1 in cardiac myocytes. Fat arrow, intercalated disc; thin arrow, lateral membrane; small arrow, t-tubules. (C and D) Lack of Popdc1 expression in the epicardium and subepicardium (arrow in C) and in coronary arteries (arrow in D). (E–G) The expression levels of Popdc1 in the atrioventricular node (AVN) and His bundle (His) are higher than in the ventricular septum (VS) and equal to the level in the atria (AT). Immunohistochemical staining of mouse hearts using antibodies directed against (E) Popdc1 and (F) HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4). (G) Merge of Popdc1 and HCN4 staining.
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 . 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 .
Figure 3. Models of Popdc protein function(A) Switch model: Popdc protein might act as a switch that activates or inactivates proteins with which it forms a complex. The example depicted is the potassium channel TREK-1, which forms a complex with Popdc protein. Binding of cAMP may induce a change in protein conformation, leading to a modulation of the open probability of the associated ion channel. (B) Cargo model: Popdc proteins are found in cytoplasmic vesicles and may regulate the transport of effector proteins to the plasma membrane, which may also involve Cav3, with which Popdc proteins form a complex. Both models are supported by protein–protein interaction data of Popdc proteins with TREK-1 and Cav3 [6,35].