Structure of Yeast Regulatory Subunit: A Glimpse into the Evolution of PKA Signaling

SummaryThe major cAMP receptors in eukaryotes are the regulatory (R) subunits of PKA, an allosteric enzyme conserved in fungi through mammals. While mammals have four R-subunit genes, Saccharomyces cerevisiae has only one, Bcy1. To achieve a molecular understanding of PKA activation in yeast and to explore the evolution of cyclic-nucleotide binding (CNB) domains, we solved the structure of cAMP-bound Bcy1(168-416). Surprisingly, the relative orientation of the two CNB domains in Bcy1 is very different from mammalian R-subunits. This quaternary structure is defined primarily by a fungi-specific sequence in the hinge between the αB/αC helices of the CNB-A domain. The unique interface between the two CNB domains in Bcy1 defines the allosteric mechanism for cooperative activation of PKA by cAMP. Some interface motifs are isoform-specific while others, although conserved, play surprisingly different roles in each R-subunit. Phylogenetic analysis shows that structural differences in Bcy1 are shared by fungi of the subphylum Saccharomycotina.

Graphical AbstractFigure optionsDownload high-quality image (142 K)Download as PowerPoint slideHighlights
► This is the first structure of fungal PKA R-subunit (S.cerevisiae Bcy1 [168-416])
► Individual cAMP binding domains (CNB) are similar to the mammalian counterparts
► Orientation and interface between the two CNB domains is very different in Bcy1
► Bcy1 structure is representative for the subphylum Saccharomycotina