期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 10, 页码 2756-2761出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1517549113
关键词
mouse mutant; behavior; protein stability; circadian period; genetic interaction
资金
- US Department of Energy Office of Biological and Environmental Research
- US NIH project MINOS [R01 GM105404]
- Medical Research Council, United Kingdom [MC_U142684173, MC_U105170643]
- Sixth Framework Project EUCLOCK Grant [018741]
- US NIH Grant [R01 GM107029]
- W. M. Keck Foundation [001768]
- US NIH Center for Research Resources [S10 RR020939]
- MRC [MC_U105170643, MC_U142684173] Funding Source: UKRI
- Medical Research Council [MC_U142684173, MC_U105170643, 1576465] Funding Source: researchfish
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 1 epsilon (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.
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