The Tails of Protein Kinase A

Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, Ca and Cb, and four functionally nonredundant R-subunits (RIa, RIb, RIIa, RIIb). In addition to binding to and being regulated by the R-subunits, the C -subunits are regulated by two tail regions that each wrap around the N-and C-lobes of the kinase core. Although the C-terminal (Ct-) tail is classified as an intrinsically disordered region (IDR), the N-terminal (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 PKA, PKG, and protein kinase C protein kinase group (AGC) kinases, the Nt-tail has evolved more recently and is highly variable in vertebrates. Surprisingly and in contrast to the kinase core and the Ct-tail, the entire Nttail is not conserved in nonmammalian PKAs. In particular, in humans, Cb actually represents a large family of C-subunits that are highly variable in their Nt-tail and also expressed in a highly tissue-specific manner. Although we know so much about the Ca1-subunit, we know almost nothing about these Cb isoforms wherein 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 nonredundant with the Ca isoforms. Imaging in retina also supports nonredundant 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/Cttails) affect the structure and regulate the function of the kinase core and show the combinatorial variations that are introduced into the Nt-tail of the Ca-and Cb-subunits in contrast to the Cttail, which is conserved across the entire AGC subfamily of protein kinases.

Automated summary

Protein kinase A (PKA) is a holoenzyme consisting of regulatory (R) subunit dimers and two catalytic (C) subunits, with different families of C subunits (Ca and Cb) and four nonredundant R subunits (RIa, RIb, RIIa, RIIb). The N- and C-terminal tails of PKA influence the structure and function of the kinase core, with the Nt-tails showing combinatorial variations in Ca and Cb subunits compared to the conserved Ct-tail. The Cb isoforms, particularly Cb2 in lymphocytes, and Cb3 and Cb4 in the brain, play important and nonredundant roles in PKA signaling, with isoform-specific localization to mitochondria.