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.

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

“…The POPDC protein family encompasses 3 medium‐sized, transmembrane proteins, POPDC1, POPDC2, and POPDC3, that are glycosylated to variable extent in different tissues . The proteins and their genes were first described in 1999 to 2000 and reported to be abundantly expressed in heart and skeletal muscle .…”

“…POPDC proteins have a short extracellular amino terminus, 3 transmembrane domains, and a conserved Popeye domain that, together with the carboxy‐terminal domain (CTD), is localized in the cytoplasmic part of the protein . The Popeye domain functions as a cyclic adenosine monophosphate (cAMP)–binding domain, which displays a similar 2‐dimensional and 3‐dimensional (3D) structure but no homology to other vertebrate cAMP‐binding proteins at the sequence level . POPDC proteins represent a novel class of cAMP effector proteins, which modulate membrane trafficking of interacting proteins .…”

“…6 The POPDC protein family encompasses 3 mediumsized, transmembrane proteins, POPDC1, POPDC2, and POPDC3, that are glycosylated to variable extent in different tissues. 7 The proteins and their genes were first described in 1999 to 2000 and reported to be abundantly expressed in heart and skeletal muscle. 8,9 POPDC proteins have a short extracellular amino terminus, 3 transmembrane domains, and a conserved Popeye domain that, together with the carboxy-terminal domain (CTD), is localized in the cytoplasmic part of the protein.…”

“…10 The Popeye domain functions as a cyclic adenosine monophosphate (cAMP)-binding domain, which displays a similar 2-dimensional and 3-dimensional (3D) structure but no homology to other vertebrate cAMP-binding proteins at the sequence level. 7 POPDC proteins represent a novel class of cAMP effector proteins, which modulate membrane trafficking of interacting proteins. 7,11 Knockdown of popdc1 and popdc2 produces a muscular dystrophy and cardiac arrhythmia phenotype in zebrafish.…”

“…7 POPDC proteins represent a novel class of cAMP effector proteins, which modulate membrane trafficking of interacting proteins. 7,11 Knockdown of popdc1 and popdc2 produces a muscular dystrophy and cardiac arrhythmia phenotype in zebrafish. 4,12 In mouse models, loss of Popdc1 and Popdc2 preferentially exerts effects on the heart, although a regeneration phenotype in skeletal muscle has been described.…”