The Popeye domain containing gene family encoding a family of cAMP-effector proteins with important functions in striated muscle and beyond

Abstract

The Popeye domain containing (POPDC) gene family encodes a novel class of membrane-bound cyclic AMP effector proteins. POPDC proteins are abundantly expressed in cardiac and skeletal muscle. Consistent with its predominant expression in striated muscle, Popdc1 and Popdc2 null mutants in mouse and zebrafish develop cardiac arrhythmia and muscular dystrophy. Likewise, mutations in POPDC genes in patients have been associated with cardiac arrhythmia and muscular dystrophy phenotypes. A membrane trafficking function has been identified in this context. POPDC proteins have also been linked to tumour formation. Here, POPDC1 plays a role as a tumour suppressor by limiting c-Myc and WNT signalling. Currently, a common functional link between POPDC's role in striated muscle and as a tumour suppressor is lacking. We also discuss several alternative working models to better understand POPDC protein function.

Keywords: Atrioventricular block; Limb-girdle muscular dystrophy; Membrane trafficking; Popeye domain containing genes; Sinus node disease; Tumour suppressor; cAMP.

Fig. 1

The cAMP signalling pathway. Activation of adenylyl cyclase (AC) by G-coupled receptors (GPCR) via Gs leads to an accumulation of cAMP, which is bound by a number of different cAMP effector proteins, namely HCN channels and POPDC proteins, which are both membrane-bound, while EPAC and PKA are cytoplasmic proteins. PKA is bound by a diverse group of anchor proteins (AKAP), which also recruit PDE isoforms forming a nanodomain. PKA activation and substrate phosphorylation is under tight spatiotemporal control. There are a large number of AKAP proteins in cells creating many different cAMP nanodomains in different subcellular compartments (grey halo). AKAP proteins also bind other signalling molecules forming a platform also allowing cross-talk between signalling pathways

Fig. 2

Structure and Function of the Popeye domain containing proteins. a Schematic of the general, linear structure of the POPDC proteins. The short amino terminus contains one (POPDC2 or POPDC3) or two (POPDC) N-glycosylation sites. Three transmembrane domains (TM) are followed by the intracellular Popeye domain, which contains the PBC, including the conserved DSPE and FQVT motifs. The putative POPDC dimerization motif (K272/K273) (Kawaguchi et al. 2008), is shown along with the proposed interaction sites of TREK1 (Schindler et al. 2016) and CAV3 (Alcalay et al. 2013). The carboxy terminus contains a number of conserved phosphorylation sites, which are subject to phosphorylation in response to adrenergic stimulation (Lundby et al. 2013). b A schematic of the quaternary structure of a membrane associated POPDC dimer. Each Popeye domain is shown bound to a molecule of cAMP (red sphere). In case of POPDC1 an intramolecular disulphide bridge stabilises the homodimer. c A homology model of the Popeye domain of POPDC1. The conserved DSPE and FQVT motifs, part of the proposed PBC, are shown in pink, with a molecule of cAMP bound. d An enlargement of the cAMP bound PBC from the model shown in c. The position of the DSPE and FQVT motifs are indicated. The models in C and D were created using the Phyre 2 algorithm (Kelley et al. 2015) and the image was rendered using iCn3D (iCn3D 2016)

Fig. 3

Four proposed working models of the role of POPDC proteins in the cAMP pathway. a The switch model. Binding of cAMP to POPDC leads to a direct change in activity of an interaction partner e.g. opening of TREK1. b The sponge model. The binding of cAMP to POPDC proteins leads to a reduction in the local cAMP concentration. This reduces activation of other proteins in the cAMP pathway, in this case PKA. A lowering of POPDC expression (such as in null mutants), or alternatively a reduction in the cAMP binding affinity (such as in missense mutations found in patients), leads to an increase in the free cAMP concentration and therefore results in stronger and more sustained activation of cAMP effector proteins. c Cargo model. This model proposes that cAMP influences the POPDC protein’s role in modulating membrane influences the POPDC protein’s role in modulating membrane expression of interaction partners. The exact effect of cAMP binding on vesicle transport and membrane trafficking is currently not fully understood. d The shield model. This model builds on the switch model and suggests that cAMP binding to the Popeye domain may lead to indirect downstream effects, possibly via phosphorylation of the POPDC proteins. For example, in the unbound state POPDC proteins may shield interaction partners from being accessed by kinases, with this inhibition being reduced after cAMP binding to the Popeye domain. How the phosphorylation and conformational changes of POPDC proteins after cAMP mediate downstream effects is still unclear