Journal article
The Tails of Protein Kinase A
Publication Details
Authors: | Taylor, S.; Søberg, K.; Kobori, E.; Wu, J.; Pautz, S.; Herberg, F.; Skålhegg, B. |
Publication year: | 2022 |
Journal: | Molecular Pharmacology |
Pages range : | 219-225 |
Volume number: | 101 |
Issue number: | 4 |
ISSN: | 0026-895X |
eISSN: | 1521-0111 |
DOI-Link der Erstveröffentlichung: |
Abstract
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\textgreeka and C\textgreekb, and four functionally nonredundant R-subunits (RI\textgreeka, RI\textgreekb, RII\textgreeka, RII\textgreekb). 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\textgreekb 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\textgreeka1-subunit, we know almost nothing about these C\textgreekb isoforms wherein C\textgreekb2 is highly expressed in lymphocytes, and C\textgreekb3 and C\textgreekb4 isoforms account for $\sim$50{\%} of PKA signaling in brain. Based on recent disease mutations, the C\textgreekb proteins appear to be functionally important and nonredundant with the C\textgreeka isoforms. Imaging in retina also supports nonredundant roles for C\textgreekb 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\textgreeka- and C\textgreekb-subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.
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\textgreeka and C\textgreekb, and four functionally nonredundant R-subunits (RI\textgreeka, RI\textgreekb, RII\textgreeka, RII\textgreekb). 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\textgreekb 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\textgreeka1-subunit, we know almost nothing about these C\textgreekb isoforms wherein C\textgreekb2 is highly expressed in lymphocytes, and C\textgreekb3 and C\textgreekb4 isoforms account for $\sim$50{\%} of PKA signaling in brain. Based on recent disease mutations, the C\textgreekb proteins appear to be functionally important and nonredundant with the C\textgreeka isoforms. Imaging in retina also supports nonredundant roles for C\textgreekb 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\textgreeka- and C\textgreekb-subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.
