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, Cα and Cβ, and four functionally nonredundant R-subunits (RIα, RIβ, RIIα, RIIβ). 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, Cβ 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 Cα1-subunit, we know almost nothing about these Cβ isoforms wherein Cβ2 is highly expressed in lymphocytes, and Cβ3 and Cβ4 isoforms account for ∼50% of PKA signaling in brain. Based on recent disease mutations, the Cβ proteins appear to be functionally important and nonredundant with the Cα isoforms. Imaging in retina also supports nonredundant roles for Cβ as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling.

中文翻译：

---

蛋白激酶 A 的尾巴

蛋白激酶 A (PKA) 是一种全酶，由调节 (R)-亚基二聚体和两个催化 (C)-亚基组成。有两个主要的 C 亚基家族，C α和 C β，以及四个功能上非冗余的 R 亚基（RI α、RI β、RII α、RII β). 除了与 R 亚基结合并受其调节外，C 亚基还受两个尾部区域的调节，每个区域都环绕着激酶核心的 N 叶和 C 叶。虽然 C 端 (Ct-) 尾部被归类为本质上无序的区域 (IDR)，但 N 端 (Nt-) 尾部由两侧为短 IDR 的强螺旋主导。Ct-tail 是所有 PKA、PKG 和蛋白激酶 C 蛋白激酶组 (AGC) 激酶的保守和高度调节特征，与此相反，Nt-tail 最近才进化并且在脊椎动物中高度可变。令人惊讶的是，与激酶核心和 Ct 尾部相比，整个 Nt 尾部在非哺乳动物 PKA 中并不保守。特别是，在人类中，C β实际上代表了一大类 C 亚基，它们的 Nt 尾部高度可变，并且还以高度组织特异性的方式表达。尽管我们对 C α 1 亚基知之甚多，但我们对这些 C β亚型几乎一无所知，其中 C β 2 在淋巴细胞中高度表达，而 C β 3 和 C β 4 亚型占 PKA 信号通路的 ~50%脑。基于最近的疾病突变，C β蛋白似乎在功能上很重要，并且与 C α亚型无关。视网膜成像也支持 C β的非冗余作用以及线粒体的亚型特异性定位。这代表了 PKA 信号的新领域。