Cyclic nucleotide-binding domains in proteins having diverse functions.

Abstract

Since the discovery of cAMP in the 1950s and the subsequent identification of cGMP, the role of these second messengers in mediating cellular function has been a major theme of research in biology. An important aspect of this research has been the identification and characterization of cyclic nucleotide receptors. For more than two decades, the bacterial CAMP-regulated catabolite gene activator protein (CAP),' and the eukaryotic CAMPdependent protein kinase (CAMP kinase) and cGMP-dependent protein kinase (cGMP kinase), have been the subjects of intensive investigations. CAP is a helix-turn-helix DNA-binding protein (see Refs. 1-3), and cAMP kinase is considered to be a prototypical protein kinase (see Refs. 4-6). The cyclic nucleotide-dependent protein kinases were recognized as homologous enzymes because of their similar functions and amino acid compositions (7). It was not apparent, however, that the cyclic nucleotidebinding domains of the protein kinases and CAP shared a common structural heritage until after their amino acid sequences had been determined (8). The overly simplistic view that the protein kinases mediated all of the effects of cAMP and cGMP in eukaryotic tissues has been amended with the discovery of new types of cyclic nucleotide receptors. These include cyclic nucleotide-gated cation channels (9-ll), cGMP-binding cyclic nucleotide phosphodiesterases (PDEs) (12), and the extracellular cAMP receptors (CARS) from slime mold (13, 14). The latter two classes of proteins are apparently unrelated to CAP and the protein kinases. It is now believed that cyclic nucleotides have a diversified portfolio of binding proteins through which a wide range of cellular processes can be regulated.