Abstract
Cryptochromes (CRYs) are composed of a core domain with structural similarity to photolyase and a distinguishing C-terminal extension. While plant and fly CRYs act as circadian photoreceptors, using the C terminus for light signaling, mammalian CRY1 and CRY2 are integral components of the circadian oscillator. However, the function of their C terminus remains to be resolved. Here, we show that the C-terminal extension of mCRY1 harbors a nuclear localization signal and a putative coiled-coil domain that drive nuclear localization via two independent mechanisms and shift the equilibrium of shuttling mammalian CRY1 (mCRY1)/mammalian PER2 (mPER2) complexes towards the nucleus. Importantly, deletion of the complete C terminus prevents mCRY1 from repressing CLOCK/BMAL1-mediated transcription, whereas a plant photolyase gains this key clock function upon fusion to the last 100 amino acids of the mCRY1 core and its C terminus. Thus, the acquirement of different (species-specific) C termini during evolution not only functionally separated cryptochromes from photolyase but also caused diversity within the cryptochrome family.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors
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Amino Acid Sequence
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Animals
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Arabidopsis Proteins / metabolism
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Base Sequence
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CLOCK Proteins
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Cell Cycle Proteins
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Cell Nucleus / metabolism
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Cells, Cultured
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Circadian Rhythm / physiology*
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Conserved Sequence
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Cryptochromes
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Deoxyribodipyrimidine Photo-Lyase / metabolism
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Evolution, Molecular*
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Flavoproteins / genetics
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Flavoproteins / metabolism*
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Gene Expression Regulation
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Mammals
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Mice
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Molecular Sequence Data
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Nuclear Localization Signals
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Nuclear Proteins / metabolism
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Period Circadian Proteins
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Protein Structure, Tertiary
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Protein Transport
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Transcription, Genetic
Substances
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ARNTL Transcription Factors
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Arabidopsis Proteins
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Bmal1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Cry1 protein, mouse
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Cry2 protein, mouse
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Cryptochromes
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Flavoproteins
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Nuclear Localization Signals
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Nuclear Proteins
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Per2 protein, mouse
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Period Circadian Proteins
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Trans-Activators
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Transcription Factors
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CLOCK Proteins
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Clock protein, mouse
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Deoxyribodipyrimidine Photo-Lyase