title: A Period2 Phosphoswitch Regulates and Temperature Compensates Circadian Period.
abstract: Period (PER) protein phosphorylation is a critical regulator of circadian period, yet an integrated understanding of the role and interaction between phosphorylation sites that can both increase and decrease PER2 stability remains elusive. Here, we propose a phosphoswitch model, where two competing phosphorylation sites determine whether PER2 has a fast or slow degradation rate. This mathematical model accurately reproduces the three-stage degradation kinetics of endogenous PER2. We predict and demonstrate that the phosphoswitch is intrinsically temperature sensitive, slowing down PER2 degradation as a result of faster reactions at higher temperatures. The phosphoswitch provides a biochemical mechanism for circadian temperature compensation of circadian period. This phosphoswitch additionally explains the phenotype of Familial Advanced Sleep Phase (FASP) and CK1ε(tau) genetic circadian rhythm disorders, metabolic control of PER2 stability, and how drugs that inhibit CK1 alter period. The phosphoswitch provides a general mechanism to integrate diverse stimuli to regulate circadian period.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; Mathematical Biosciences Institute, The Ohio State University, Columbus, OH 43210, USA; Department of Mathematics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jae Kyoung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Gracie Wee Ling
authors.initials: GW
authors.lastname: Eng
authors.affiliation: Department of Mathematics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: forger@umich.edu.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Forger
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: david.virshup@duke-nus.edu.sg.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000818:Animals; D002460:Cell Line; D002940:Circadian Rhythm; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D059748:Proteolysis; D013696:Temperature
chemical_list: C513312:Per2 protein, mouse; D056950:Period Circadian Proteins