Jonathan Philpott

UC Santa Cruz

“Molecular mechanisms of period control within the mammalian circadian clock”

My current predoctoral research focuses on the molecular level details of mammalian circadian rhythms, particularly the interaction between the clock proteins PERIOD2 (PER2) and Casein Kinase Id (CK1d). The results from my research will improve our understanding of how timekeeping is set by the activity of these proteins at an unprecedented level of detail using an innovative NMR and structure-based approach complemented by cell biology.

ABSTRACT

PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the Familial Advanced Sleep Phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1δ. Co-crystal structures reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1δ. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortening circadian period in human cells.
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