PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period

Philpott, J. M.; Freeberg, A. M.; Park, J.; Lee, K.; Ricci, C. G.; Hunt, S. R.; Narasimamurthy, R.; Segal, D. H.; Robles, R.; Cao, Y. D.; Tripathi, S.; McCammon, J. A.; Virshup, D. M.; Chiu, J. C.; Lee, C.; Partch, C. L.

doi:10.1101/2022.06.24.497549

bioRxiv · 10.1101/2022.06.24.497549

PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period

Philpott, J. M.·Freeberg, A. M.·Park, J.·Lee, K.·Ricci, C. G.·Hunt, S. R.·Narasimamurthy, R.·Segal, D. H.·Robles, R.·Cao, Y. D.·Tripathi, S.·McCammon, J. A.·Virshup, D. M.·Chiu, J. C.·Lee, C.·Partch, C. L.

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Abstract

PERIOD (PER) and Casein Kinase 1{delta} regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1{delta} 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 CK1{delta}. Co-crystal structures in conjunction with accelerated molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1{delta}. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortens circadian period in human cells. We found that Drosophila PER also regulates CK1{delta} via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.

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Philpott, J. M., Freeberg, A. M., Park, J., Lee, K., Ricci, C. G., Hunt, S. R., Narasimamurthy, R., Segal, D. H., Robles, R., Cao, Y. D., Tripathi, S., McCammon, J. A., Virshup, D. M., Chiu, J. C., Lee, C., Partch, C. L.. 2022-06-26. PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period. https://doi.org/10.1101/2022.06.24.497549

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