Structure of yeast regulatory subunit: a glimpse into the evolution of PKA signaling.
The 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.
Department of Biological Chemistry, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, 1428 Buenos Aires, Argentina.
Jimena
J
Rinaldi
Jian
J
Wu
Jie
J
Yang
Corie Y
CY
Ralston
Banumathi
B
Sankaran
Silvia
S
Moreno
Susan S
SS
Taylor
D016000:Cluster Analysis; D003461:Crystallography; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D019143:Evolution, Molecular; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010802:Phylogeny; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D021122:Protein Subunits; D017868:Cyclic AMP-Dependent Protein Kinases