6533b872fe1ef96bd12d39bb

RESEARCH PRODUCT

Interaction of Circadian Clock Proteins CRY1 and PER2 Is Modulated by Zinc Binding and Disulfide Bond Formation

Roman KlemzChristian BendaAchim KramerAstrid GrudzieckiThomas WallachIra SchmalenJ. Rajan PrabuEva WolfSilke Reischl

subject

Models Molecularendocrine systemanimal structuresPeriod (gene)Molecular Sequence DataCircadian clockBiologyCrystallography X-RayGeneral Biochemistry Genetics and Molecular BiologyMiceCryptochromeAnimalsProtein Interaction Domains and MotifsAmino Acid SequenceCircadian rhythmBinding siteBiochemistry Genetics and Molecular Biology(all)F-Box ProteinsPeriod Circadian ProteinsRecombinant ProteinsCryptochromesPER2ZincBiochemistryFAD bindingBiophysicsPeriod Circadian ProteinsSequence Alignment

description

SummaryPeriod (PER) proteins are essential components of the mammalian circadian clock. They form complexes with cryptochromes (CRY), which negatively regulate CLOCK/BMAL1-dependent transactivation of clock and clock-controlled genes. To define the roles of mammalian CRY/PER complexes in the circadian clock, we have determined the crystal structure of a complex comprising the photolyase homology region of mouse CRY1 (mCRY1) and a C-terminal mouse PER2 (mPER2) fragment. mPER2 winds around the helical mCRY1 domain covering the binding sites of FBXL3 and CLOCK/BMAL1, but not the FAD binding pocket. Our structure revealed an unexpected zinc ion in one interface, which stabilizes mCRY1-mPER2 interactions in vivo. We provide evidence that mCRY1/mPER2 complex formation is modulated by an interplay of zinc binding and mCRY1 disulfide bond formation, which may be influenced by the redox state of the cell. Our studies may allow for the development of circadian and metabolic modulators.

yearjournalcountryeditionlanguage
2014-05-01Cell
https://doi.org/10.1016/j.cell.2014.03.057