The Tails of Protein Kinase A

Abstract

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 tails-regions 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 highly variable in vertebrates. Surprisingly and in contrast to the kinase core and the Ct-Tail, the entire Nt-tail is not conserved in non-mammalian 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. While we know so much about the C1 subunit, we know almost nothing about these C isoforms where 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 non-redundant with the C isoforms. Imaging in retina also supports non-redundant roles for C as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling.

Protein Kinase A in cellular migration—Niche signaling of a ubiquitous kinase

“…An example of such a contextual protein in cell migration is Protein Kinase A (PKA), a promiscuous serine/threonine kinase involved in innumerable cellular and biochemical processes. PKA is a heterotetrameric holoenzyme in which two catalytic subunits from two major families, Cα and Cβ (plus a third, rarer Cγ isoform) combine with homodimers formed by any of four R-subunits (RIα, RIβ, RIIα, RIIβ) to form a number of distinct, functionally nonredundant R2:C2 holoenzymes ( Taylor et al, 2004 ; Taylor et al, 2005 ; Taylor et al, 2013 ; Taylor et al, 2022 ). Classically, however, two main subtypes of PKA are specified by the inclusion of either RI or RII regulatory subunits, each having nearly ubiquitous expression, but distinct allosteric properties, anchoring, and cellular localization, as expertly and extensively reviewed elsewhere ( Taylor et al, 2013 ; Turnham and Scott, 2016 ; Gold, 2019 ; Michel and Scott, 2022 ; Taylor et al, 2022 ).…”

“…PKA is a heterotetrameric holoenzyme in which two catalytic subunits from two major families, Cα and Cβ (plus a third, rarer Cγ isoform) combine with homodimers formed by any of four R-subunits (RIα, RIβ, RIIα, RIIβ) to form a number of distinct, functionally nonredundant R2:C2 holoenzymes ( Taylor et al, 2004 ; Taylor et al, 2005 ; Taylor et al, 2013 ; Taylor et al, 2022 ). Classically, however, two main subtypes of PKA are specified by the inclusion of either RI or RII regulatory subunits, each having nearly ubiquitous expression, but distinct allosteric properties, anchoring, and cellular localization, as expertly and extensively reviewed elsewhere ( Taylor et al, 2013 ; Turnham and Scott, 2016 ; Gold, 2019 ; Michel and Scott, 2022 ; Taylor et al, 2022 ). Canonically, PKA is activated when cAMP binds to the regulatory subunits triggering release of the catalytic subunits [though recent work has challenged this cAMP gated free-release dogma ( Smith et al, 2013 ; Smith et al, 2017 ; Isensee et al, 2018 )] as reviewed in ( Gold, 2019 ).…”

An auto-inhibited state of protein kinase G and implications for selective activation

“…The C-terminal tails of AGC kinases contribute to the overall fold and catalytic function (Kannan et al, 2007) and is important for kinase assembly and regulation (Taylor et al, 2021). In PKG, the C-terminal tail interacts directly with the kinase core ( Figure 3D ): D665 of the C-tail forms a strong salt bridge with R466 of the αD helix, and D467 stabilizes the position of R466 with a hydrogen bond.…”

“…The C-terminal tails of AGC kinases contribute to the overall fold and catalytic function (Kannan et al, 2007) and is important for kinase assembly and regulation (Taylor et al, 2021).…”

Connecting sequence features within the disordered C-terminal linker ofB. subtilisFtsZ to functions and bacterial cell division

“…Of particular interest are IDRs tethered to folded domains that are enzymes (7, 13, 14). Several studies demonstrate that IDRs tethered to folded domains can function as autoregulators (12), specifically as autoinhibitors of enzymatic activities (13, 15, 16). One such example is the C-terminal tail (CTT) of the essential GTPase that controls and regulates bacterial cell division (17).…”