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Early Doors (Edo) Mutant Mouse Reveals the Importance of Period 2 (PER2) PAS Domain Structure for Circadian Pacemaking

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Early Doors (Edo) Mutant Mouse Reveals the Importance of Period 2 (PER2) PAS Domain Structure for Circadian Pacemaking Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking Stefania Militia,1, Elizabeth S. Maywoodb,1, Colby R. Sandatec, Johanna E. Cheshamb, Alun R. Barnarda,2, Michael J. Parsonsa, Jennifer L. Viberta, Greg M. Joynsona, Carrie L. Partchc, Michael H. Hastingsb, and Patrick M. Nolana,3 aMedical Research Council Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, United Kingdom; bDivision of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom; and cDepartment of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064 Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved January 26, 2016 (received for review September 2, 2015) The suprachiasmatic nucleus (SCN) defines 24 h of time via a kinase 1e (Csnk1e) (14) is a hypermorph that accelerates the clock transcriptional/posttranslational feedback loop in which trans- of rodents (15). Thus, phosphorylation, PER protein stability, and activation of Per (period) and Cry (cryptochrome) genes by BMAL1– circadian period are intimately linked (16). CLOCK complexes is suppressed by PER–CRY complexes. The Current knowledge of the structural basis of circadian tran- molecular/structural basis of how circadian protein complexes scription and its repression is limited, but it is becoming clear function is poorly understood. We describe a novel N-ethyl-N-nitro- that modular PAS domains form protein interactions that are sourea (ENU)-induced mutation, early doors (Edo), in the PER-ARNT- important for progression of the circadian TTFL. The crystal SIM (PAS) domain dimerization region of period 2 (PER2) (I324N) structures of mouse CLOCK and BMAL1 have revealed how that accelerates the circadian clock of Per2Edo/Edo mice by 1.5 h. tandem PAS domains contribute to the formation of the dimeric Structural and biophysical analyses revealed that Edo alters the transcription factor (17). PAS domains are also found in circadian packing of the highly conserved interdomain linker of the PER2 negative regulators: tandem PAS domains mediate formation of PAS core such that, although PER2Edo complexes with clock proteins, PER dimers observed in vivo (18). Unlike the asymmetrical, ex- NEUROSCIENCE its vulnerability to degradation mediated by casein kinase 1e tended conformation seen in CLOCK-BMAL1, the PER PAS (CSNK1E) is increased. The functional relevance of this mutation is dimer core forms a more symmetrical and compact fold (19, 20). revealed by the ultrashort (<19 h) but robust circadian rhythms in In PER2, the PAS domain core is followed immediately by a Per2Edo/Edo;Csnk1eTau/Tau mice and the SCN. These periods are unprec- CK1e-dependent phosphodegron that recruits the E3 ubiquitin Edo edented in mice. Thus, Per2 reveals a direct causal link between the ligase β-TrCP to control PER2 stability (10, 16, 21). Thus, control molecular structure of the PER2 PAS core and the pace of SCN of PER2 repressive function and/or PER2 stability may be con- circadian timekeeping. trolled by interactions of its PAS domain core. mouse mutant | behavior | protein stability | circadian period | Significance genetic interaction In a study investigating mechanisms whereby period 2 (PER2) ircadian rhythms, as exemplified by the sleep/wake cycle, are stability can set the pace of biological rhythms, we have looked Cthe outward manifestation of a 24-h timing mechanism that at molecular, cellular, and structural features of the mouse mu- coordinates many physiological processes (1). The principal cir- tant, early doors (Edo). Early doors is a novel N-ethyl-N-nitro- cadian clock in mammals is the suprachiasmatic nucleus (SCN). sourea (ENU)-induced point mutation that shortens the circadian At a molecular level, the SCN clockwork consists of interacting period of mice by 1.5 h. The mutation results in an amino acid positive and negative transcriptional/translational feedback loops substitution in the interdomain linker between the tandem PAS (TTFLs) that drive rhythms in the RNA and protein levels of key domains of PER2. Biophysical analyses confirm that increased clock components. Heterodimers of the PER-ARNT-SIM (PAS) flexibility of this interdomain linker reduces stability of the PAS domain core. This flexibility can accelerate circadian rhythms by domain-containing transcriptional activators CLOCK and BMAL1 Edo drive rhythmic transcription of Per (period) and Cry (cryptochrome) destabilizing the PER2 protein through faster kinase-medi- Per2Edo genes by binding to E-box elements. PER proteins associate with ated degradation. Furthermore, we find that mice car- e Csnk1e Tau CRY, translocating to the nucleus to inhibit their own transcription rying the casein kinase 1 ( ) mutation have extremely by interacting with the CLOCK–BMAL1 complex (2, 3). An ad- fast but very stable circadian clocks. ditional feedback loop involves the nuclear orphan receptors REV- Author contributions: C.L.P., M.H.H., and P.M.N. designed research; S.M., E.S.M., C.R.S., ERBα (4) and RAR-related orphan receptor A (RORA) (5) that J.E.C., A.R.B., M.J.P., G.M.J., C.L.P., and M.H.H. performed research; J.L.V. contributed modify the transcription of Bmal1, thereby stabilizing and ampli- new reagents/analytic tools; E.S.M., M.J.P., J.L.V., C.L.P., M.H.H., and P.M.N. analyzed fying the CLOCK–BMAL complex-dependent oscillation. Once data; and E.S.M., C.L.P., M.H.H., and P.M.N. wrote the paper. suppressed, CLOCK–BMAL complex-mediated transactivation can The authors declare no conflict of interest. only reoccur after PER and CRY have been degraded. This article is a PNAS Direct Submission. The circadian TTFL is therefore sustained by timely synthesis Freely available online through the PNAS open access option. and degradation of PER and CRY proteins. Changes in PER sta- Data deposition: Scattering datasets, analysis, and models have been deposited with bility in flies (6, 7) and changes in PER or CRY stability in mam- BioISIS (www.bioisis.net) [deposition codes PLCSWP (PER2WT) and PLCSEP (PER2Edo)]. mals lead to a faster or slower clock (8). Phosphorylation-dependent 1S.M. and E.S.M. contributed equally to this work. licensing of PER proteins for ubiquitination and subsequent pro- 2Present address: Nuffield Department of Clinical Neurosciences, University of Oxford, teasomal degradation is a sensitive checkpoint in setting clock speed Oxford OX3 9DU, United Kingdom. (9–11). Moreover, two familial advanced sleep phase syndromes 3To whom correspondence should be addressed. Email: [email protected]. (FASPSs) are associated with site-specific phosphorylation of hu- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. man period 2 (PER2) (12, 13). Finally, the Tau mutation of casein 1073/pnas.1517549113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1517549113 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 To gain new insight into the mechanisms that determine the pace A +/+ Edo/+ Edo/Edo of the mammalian circadian clock, we used N-ethyl-N-nitrosourea 0 (ENU) mutagenesis (22). We identified a founder mouse with a L/D significantly shortened circadian period. The mutation, early doors (Edo), mapped to the Per2 gene within the linker between the Days PAS-A and PAS-B domains. PER2Edo reveals the determinative DD relationship between protein stability and circadian pacemaking, 18 and, more importantly, it reveals a structural framework within 0 48 0 48 0 48 which to understand this defining property of the circadian system. time (h) B C Results 40 m/m Per2Edo m/+ Shortens Circadian Wheel-Running Period. We screened for 23.8 genetic factors affecting overt behavioral circadian rhythms 30 +/+ by monitoring daily wheel-running activity in progeny of ENU 20 22.8 mutagenized mice. Within G1/dominant inheritance screens, we Frequency 10 identified a mouse with a significantly shortened circadian period DD (h) Tau (τDD) (Fig. 1A). Test mating confirmed semidominant herita- 0 21.8 bility of the phenotype, with the following mean circadian periods +/+ Edo/+ Edo/Edo 21 22 23 24 recorded in outcross/intercross offspring: WT τDD of ∼23.6 h, Tau DD (h) CGG CCTTTTAAAG CCC CC AG τ ∼ τ ∼ heterozygote DD of 23 h, and homozygote DD of 22 h (Fig. D E 1 B and C). Homozygotes also displayed a clear advanced phase of C57BL/6 entrainment, with activity onsets preceding the onset of the dark Chr 1 BALB/c phase by several hours. This mutant line was named early doors C57BL/6+BALB/c (Edo; Mouse Genome Informatics accession ID MGI:3606316). 5 2 3 3 1 1 2 2 rs3706173 41.9 Mb CGG CCTTAG AAACCC CCTAG The mutation was mapped by genetic linkage analysis to a 76.5- rs3677697 80.1 Mb Mb region of mouse chromosome 1 (Fig. 1D). Within this region rs3680832 118.6 Mb Per2 lies the period homolog 2 (Per2). With an established role in the rs3724524 156.6 Mb circadian oscillator, this gene was selected as a candidate, and the rs3699344 190.9 Mb coding regions of Per2 were resequenced in a mutant animal. Se- quencing revealed a T-to-A transversion in exon 9 of the gene (Fig. F E PAS NES CK1 NLS CRY binding 1 ). This nonsynonymous missense mutation results in an Ile-to- Per2 AB Asn substitution at residue 324 (I324N) of PER2, which lies in the interdomain linker between two tandem PAS domains (Fig. 1F). The residue is highly conserved within the protein sequence of all Edo mouse Per genes and in the orthologous genes of other vertebrates. Mus_musculus_Per2 Rattus_norvegicus Homo_sapiens Edo Bos_taurus Per2 mPer2 Gallus_gallus Is a Gain-of-Function Allele. Several null alleles of Xenopus_tropicalis Danio_rerio have been described, and have been shown to have either no effect Per1_Mus_musculus on circadian period (23) or to disrupt rhythms (24, 25).
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