New kids on the block: The Popeye domain containing (POPDC) protein family acting as a novel class of cAMP effector proteins in striated muscle

Abstract

The cyclic 3',5'-adenosine monophosphate (cAMP) signalling pathway constitutes an ancient signal transduction pathway present in prokaryotes and eukaryotes. Previously, it was thought that in eukaryotes three effector proteins mediate cAMP signalling, namely protein kinase A (PKA), exchange factor directly activated by cAMP (EPAC) and the cyclic-nucleotide gated channels. However, recently a novel family of cAMP effector proteins emerged and was termed the Popeye domain containing (POPDC) family, which consists of three members POPDC1, POPDC2 and POPDC3. POPDC proteins are transmembrane proteins, which are abundantly present in striated and smooth muscle cells. POPDC proteins bind cAMP with high affinity comparable to PKA. Presently, their biochemical activity is poorly understood. However, mutational analysis in animal models as well as the disease phenotype observed in patients carrying missense mutations suggests that POPDC proteins are acting by modulating membrane trafficking of interacting proteins. In this review, we will describe the current knowledge about this gene family and also outline the apparent gaps in our understanding of their role in cAMP signalling and beyond.

Keywords: Atrioventricular block; Heart disease; Limb-girdle muscular dystrophy; Popeye domain containing; Protein interaction; Stress-induced bradycardia; cAMP signalling.

Fig. 1

The cAMP signalling pathway in cardiac myocytes. In response to adrenergic stimulation via β1- or β2-adrenergic receptors (β1AR, β2AR), cAMP is synthesized by adenylyl cyclases (AC) and degraded by phosphodiesterases (PDEs). The effector proteins protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) are part of signalosomes, which are organized by A protein kinase associated proteins (AKAPs). Target proteins, which are getting phosphorylated by PKA are often part of AKAP-dependent signalosomes. Popeye domain containing (POPDC) proteins are localized to many different subcellular compartments, some of which are also shared by other cAMP binding proteins. It is unknown whether POPDC proteins are part of the same signalosome complex as other cAMP effector proteins. Like PKA and EPAC proteins, POPDC proteins are also found in the nucleoplasm probably lacking the transmembrane domains (ΔTM-POPDC).

Fig. 2

Structural modelling of the Popeye domain containing proteins. (A) Secondary structure prediction of POPDC proteins using Psipred . In each isoform, a short (26–47 residues) extracellular domain (ECD) is present, which harbors one or two N-glycosylation motifs (asterisks) followed by three transmembrane domains (TM1–3). A large part of the cytoplasmic domain consists of the Popeye domain, which is close to 50% similar between family members. The carboxy-terminal domain (CTD) is most variable part of the POPDC proteins and distinct between isoforms. (B) 3-D models of POPDC1, POPDC2, and POPDC3. The models were produced with the help of the Phyre 2 web portal, which predicts 3-D protein structures on the basis of homology modelling . The structures were visualized using the CCP4 molecular graphics program . (C,D) Demonstration of evolutionary conservation of the Popeye domain with the help of the Consurf program . (C) Cartoon and (D) Spacefill model of the Popeye domain of human POPDC1. Many invariant amino acids cluster around the PBC or are part of the lid, which is predicted to fold over the PBC when ligand is bound .

Fig. 3

Different working models of POPDC protein function. (A) Switch model. (B) Cargo model. (C) Shielding model. (D) Sponge model. See text for a further description and the experimental evidence supporting these different models of POPDC protein function.