Self-regulation of an enzyme with critical cellular functions

The laboratory of Cathy Gould, Professor Louise B. McGavok and Professor of Cell Biology and Developmental Biology, uses a multidisciplinary approach that includes structural biology, biochemistry and molecular biology to study the regulation of the CK1 enzyme family. The study, led by Sierra Kulati, a postdoc in Gould’s laboratory, was conducted in collaboration with Jun-Song Chen, a research assistant in cell biology and developmental biology, and scientists from Goethe University and the Consortium for Structural Genomics in Frankfurt, Germany, and Harvard. University, was published in Molecular cell.

CK1 enzymes are a family of multifunctional kinases – enzymes that can phosphorylate or add phosphate groups to other proteins – that are critical for several cellular functions, including DNA repair, endocytosis and mitotic checkpoint signaling. Regulation of CK1 enzymes is extremely important, as dysfunction of these enzymes contributes to several conditions, which include cancer, neurodegenerative diseases, and sleep disorders.

There are seven CK1 enzymes in mammals that perform different functions, but they are strongly conserved in their catalytic domain, the region responsible for phosphorylation. Gould and colleagues found that one mechanism of CK1 activity and thus one regulatory mechanism is the self-phosphorylation of a conserved amino acid residue in its catalytic domain.

The researchers further investigated how this self-phosphorylation regulates activity and found that phosphorylation at this site altered the substrate specificity of CK1 enzymes. Substrate specificity refers to the determination of which other proteins will phosphorylate CK1 kinases, which in turn determines which pathways in the cell are activated. In general, the state of phosphorylation of CK1 enzymes controls their function – or dysfunction – in the cell. Determining which pathways are controlled by phosphorylated versus non-phosphorylated enzyme states is a step toward developing better treatments with fewer side effects for diseases caused by enzyme dysfunction.

Gould’s laboratory and colleagues hope to build on this work by identifying other sites of CK1 self-phosphorylation and exploring the pathways they regulate; there are several potential sites for self-phosphorylation gathered at one end of the protein, for example, that intrigue researchers. In addition, they plan to study how open phosphorylation sites work together to provide additional control under different cellular conditions, such as cellular stress.