Signaling through cAMP and cAMP-dependent Protein Kinase

Susan Taylor (UCSD)

Abstract

Protein phosphorylation is probably the most important mechanism for regulation in biology, and the protein kinases are one of the largest gene superfamilies in eukaryotic genomes. They account for 2-4% of most genomes. cAMP, on the other hand, is a universal second messenger throughout biology, and its major receptor in eukaryotic cells, cAMP-dependent Protein Kinase (PKA), is ubiquitous. Thus in PKA two major signaling mechanisms have converged. The PKA holoenzyme is an inactive tetramer comprised of a regulatory (R) subunit dimer and two catalytic (C) subunits. The PKA signaling pathway is mediated by the dynamic behavior of the PKA regulatory subunits which in the absence of cAMP wrap around the catalytic (C) subunit thereby inhibiting its catalytic activity. Binding of cAMP initiates a major conformational change that leads to the release of the active catalytic subunit. Elucidation of the holoenzyme structure has for the first time allowed us to appreciate the molecular basis for the inhibition and activation of the catalytic subunit. It also defines the C subunit, and consequently all members of the protein kinase superfamily, as scaffold proteins that interact with many inhibitors and substrate proteins though distal sites that are far from the catalytic site. PKA serves as a prototype for the entire protein kinase superfamily. By analyzing the Global Ocean Survey (GOS) genes, we have also been able to define the microbial origins of this phosphoryl transfer mechanism. At the same time we have mapped the cAMP-binding domain and found that it is also widespread in both eukaryotes and prokaryotes. Thus we have a template for extensive and diverse signaling that is mediated by phosphoryl transfer and second messengers through all phyla.

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