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The suprachiasmatic nucleus (SCN) defines 24 h of time via a transcriptional/posttranslational feedback loop in which transactivation of Per (period) and Cry (cryptochrome) genes by BMAL1-CLOCK complexes is suppressed by PER-CRY complexes. The molecular/structural basis of how circadian protein complexes function is poorly understood. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutation, early doors (Edo), in the PER-ARNT-SIM (PAS) domain dimerization region of period 2 (PER2) (I324N) that accelerates the circadian clock of Per2(Edo/Edo) mice by 1.5 h. Structural and biophysical analyses revealed that Edo alters the packing of the highly conserved interdomain linker of the PER2 PAS core such that, although PER2(Edo) complexes with clock proteins, its vulnerability to degradation mediated by casein kinase 1ε (CSNK1E) is increased. The functional relevance of this mutation is revealed by the ultrashort (<19 h) but robust circadian rhythms in Per2(Edo/Edo); Csnk1e(Tau/Tau) mice and the SCN. These periods are unprecedented in mice. Thus, Per2(Edo) reveals a direct causal link between the molecular structure of the PER2 PAS core and the pace of SCN circadian timekeeping.

Original publication

DOI

10.1073/pnas.1517549113

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

08/03/2016

Volume

113

Pages

2756 - 2761

Keywords

behavior, circadian period, genetic interaction, mouse mutant, protein stability, Amino Acid Sequence, Animals, Blotting, Western, COS Cells, Casein Kinase Iepsilon, Cercopithecus aethiops, Circadian Clocks, Circadian Rhythm, Female, HEK293 Cells, Humans, Male, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Models, Molecular, Molecular Sequence Data, Motor Activity, Mutation, Missense, Period Circadian Proteins, Protein Multimerization, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Suprachiasmatic Nucleus