The Tails of Protein Kinase A

The catalytic subunit of PKA is regulated by two tails that each wrap around the N- and C-lobes of the kinase core. While the Ct-Tail is classified as an intrinsically disordered region (IDR), the Nt-Tail is dominated by a strong helix that is flanked by short IDRs. In contrast to the Ct-Tail, which is a conserved and highly regulated feature of all AGC kinases, the Nt-Tail has evolved more recently and is not even conserved in non-mammalian PKAs. In addition, and most importantly, there is a large family of Cb subunits that are highly expressed in mammalian cells in a tissue-specific manner. While we know so much about the Ca1 subunit, we know almost nothing about these Cb isoforms where Cb2 is highly expressed in lymphocytes and Cb3 and Cb4 isoforms account for ~50% of PKA signaling in brain. Based on recent disease mutations, the Cb proteins appear to be functionally important and non-redundant with the Ca isoforms. Imaging in retina also supports non-redundant roles for Cb as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling. Significance Statement How tails and adjacent domains regulate each protein kinase is a fundamental challenge for the biological community. Here we highlight how the N- and C-terminal tails of PKA (Nt-Tails/Ct-Tails) regulate the structure and function of the kinase core and show the combinatorial variations that are introduced into the Nt-Tail of the Ca and Cb subunits of PKA in contrast to the Ct-Tail which is conserved across the entire AGC subfamily of protein kinases.