An Ancestral Mechanism of Calmodulin Binding to Cds1 Kinase Inhibits Catalytic Activity

Calmodulin is a highly conserved, calcium (Ca2+) sensor protein that is ubiquitous among eukaryotes. Ca2+ binding to Calmodulin induces a conformational change that facilitates interaction with, and activation of, serine/threonine protein kinases, including members of the CaMK family. Recently, Ca2+-Calmodulin binding to one such protein kinase, Checkpoint kinase 2 (CHK2), which is responsible for the regulation of cell cycle progression following DNA damage in mammalian cells, was shown to suppress CHK2 catalytic activity. Here, by applying biochemical, structural mass spectrometry and yeast genetic methods, we identify an analogous mode of inhibition of the fission yeast Schizosaccharomyces pombe CHK2 functional orthologue, Cds1, through direct binding of Ca2+-Calmodulin to the Cds1 kinase domain. Our studies assert an ancestral function for Calmodulin in suppressing the catalytic activity of CHK2 orthologs and highlight a mechanism by which Ca2+ flux can attenuate Cds1 catalytic activity to facilitate exit from the replication checkpoint and promote cell cycle progression.