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, C α and C β , and four functionally nonredundant R-subunits (RI α , RI β , RII α , RII β ). 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 Nt-tail is not conserved in nonmammalian PKAs. In particular, in humans, C β 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 C α 1-subunit, we know almost nothing about these C β isoforms wherein C β 2 is highly expressed in lymphocytes, and C β 3 and C β 4 isoforms account for ∼50% of PKA signaling in brain. Based on recent disease mutations, the C β proteins appear to be functionally important and nonredundant with the C α isoforms. Imaging in retina also supports nonredundant roles for C β 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) 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 C α - and C β -subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.
(Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)