The Tails of Protein Kinase A

• Published in: Molecular pharmacology Vol. 101; no. 4; pp. 219 - 225
• Main Authors: Taylor, Susan S, Søberg, Kristoffer, Kobori, Evan, Wu, Jian, Pautz, Sabine, Herberg, Friedrich W, Skålhegg, Bjørn Steen
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01-04-2022
• Subjects: Animals; Axelrod Symposium Protein Kinases in Tune - Special Section; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - genetics; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Humans; Protein Isoforms - metabolism; Protein Kinases - metabolism; Signal Transduction
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/molpharm.121.000315

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
and C
, and four functionally nonredundant R-subunits (RI
, RI
, RII
, RII
). 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
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
1-subunit, we know almost nothing about these C
isoforms wherein C
2 is highly expressed in lymphocytes, and C
3 and C
4 isoforms account for ∼50% of PKA signaling in brain. Based on recent disease mutations, the C
proteins appear to be functionally important and nonredundant with the C
isoforms. Imaging in retina also supports nonredundant roles for C
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
- and C
-subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.