Abstract

Over thirty years have passed since that first PKA structure was solved and in so many ways PKA has served as the poster child for the protein kinase superfamily. In addition to trapping each step of catalysis in a crystal lattice and solving isoform-specific holoenzyme structures, by comparing PKA to other kinases we discovered the Regulatory and Catalytic Spines. This hydrophobic core architecture provides us with a conceptual framework to better understand how all protein kinases are activated and regulated as molecular switches. Over the past three years, however, we have also made unanticipated discoveries that open some new frontiers in PKA signaling. C isoforms, for example, are virtually unexplored although they account for ~50% of PKA signaling in neurons. The biomolecular condensates formed by RI that serve as a “Sponge” for compartmentalizing cAMP is another new concept as is our discovery of a PKI -like sequence embedded in the tail of Smoothened, the GPCR that regulates Sonic hedgehog signaling. Our approach to build an interdisciplinary platform where we can move seamlessly from atomic level resolution to cells and tissues allows us to quickly build on new discoveries