3′,5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase or protein kinase A (PKA) has served as a prototype for the large family of protein kinases that are crucially important for signal transduction in eukaryotic cells. The PKA catalytic subunits are encoded by the two major genes PRKACA and PRKACB, respectively. The PRKACA gene encodes two known splice variants, the ubiquitously expressed Cα1 and the sperm-specifically expressed Cα2. In contrast, the PRKACB gene encodes several splice variants expressed in a highly cell and tissue-specific manner. The Cβ proteins are called Cβ1, Cβ2, Cβ3, Cβ4 and so-called abc variants of Cβ3 and Cβ4. Whereas Cβ1 is ubiquitously expressed, Cβ2 is enriched in immune cells and the Cβ3, Cβ4 and their abc variants are solely expressed in neuronal cells. All Cα and Cβ splice variants share a kinase-conserved catalytic core and a C-terminal tail encoded by exons 2 through 10 in the PRKACA and PRKACB genes, respectively. All Cα and Cβ splice variants with the exception of Cα1 and Cβ1 are hyper-variable at the N-terminus. Here, we will discuss how the PRKACA and PRKACB genes have developed as paralogs that encode distinct and functionally non-redundant proteins. The fact that Cα and Cβ splice variant mutations are associated with numerous diseases further opens new windows for PKA-induced disease pathologies.
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Cover Image
Cover Image
PKA Cβ: A forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies.
The N- and C-terminal tails (Nt-tail/Ct-Tail) of the PKA catalytic subunit wrap around the N-lobe (white shell) and C-lobe (tan shell) of the kinase core. The sequences differences, indicated as dots, between Cα and Cβ are mapped onto the Cα structure, these cluster around the Nt-Tail and the Ct-Tail and to regions of the core that are regulated by the tails. The Cβ isoforms created by different genes and splice variants differ only in the first exon (circle), a region in Cα that is important for targeting. For more information see the review by Taylor and colleagues (pp. 2101–2119) in this issue. Image provided by Susan Taylor.
PKA Cβ: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies
Susan S. Taylor, Maximilian Wallbott, Erik M. F. Machal, Kristoffer Søberg, Faihaa Ahmed, Jessica Bruystens, Lily Vu, Blaine Baker, Jian Wu, Francesco Raimondi, Elimelda M. Ongeri, Friedrich W. Herberg, Bjørn S. Skålhegg; PKA Cβ: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies. Biochem J 11 June 2021; 478 (11): 2101–2119. doi: https://doi.org/10.1042/BCJ20200867
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