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

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Publisher: National Academy of Sciences
Document Type: Report
Length: 6,514 words
Lexile Measure: 1350L

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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-ARNTSIM (PAS) domain dimerization region of period 2 (PER2) (I324N) that accelerates the circadian clock of [per2.sup.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.sup.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 ( mouse mutant | behavior | protein stability | circadian period | genetic interaction

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Gale Document Number: GALE|A449417898