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Proc Natl Acad Sci U S A. 2016 Mar 8;113(10):2756-61. doi: 10.1073/pnas.1517549113. Epub 2016 Feb 22.

Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking.

Author information

1
Medical Research Council Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, United Kingdom;
2
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom;
3
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064.
4
Medical Research Council Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, United Kingdom; p.nolan@har.mrc.ac.uk.

Abstract

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.

KEYWORDS:

behavior; circadian period; genetic interaction; mouse mutant; protein stability

PMID:
26903623
PMCID:
PMC4791021
DOI:
10.1073/pnas.1517549113
[Indexed for MEDLINE]
Free PMC Article

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