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Cryptochrome-Timeless structure reveals circadian clock timing mechanisms
Open accessPreprint — published as 10.1038/s41586-023-06009-4 · Paper page
Abstract
Circadian rhythms influence many behaviors and diseases 1, 2 . They arise from oscillations in gene expression caused by repressor proteins that directly inhibit transcription of their own genes. The fly circadian clock offers a valuable model for studying these processes, wherein Timeless (TIM) plays a critical role in mediating nuclear entry of the transcriptional repressor Period (PER) and the photoreceptor Cryptochrome (CRY) entrains the clock by triggering TIM degradation in light 2, 3 . The cryo-EM structure of the CRY:TIM complex reveals how a light-sensing cryptochrome recognizes its target. CRY engages a continuous core of N-terminal TIM armadillo (ARM) repeats, resembling how photolyases recognize damaged DNA, and binds a C-terminal TIM helix reminiscent of the interactions between light-insensitive CRYs and their partners in mammals. The structure highlights how the CRY flavin cofactor undergoes conformational changes that couple to large-scale rearrangements at the molecular interface, and how a phosphorylated segment in TIM may impact clock period by regulating the binding of importin-α and the nuclear import of TIM:PER 4, 5 . Moreover, the structure reveals that the TIM N-terminus inserts into the restructured CRY pocket to replace the autoinhibitory C-terminal tail released by light, thereby providing a possible explanation for how the LS-TIM polymorphism adapts flies to different climates 6, 7 .
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Metadata
- Authors
- Lin, C., Feng, S., DeOliveira, C. C., & Crane, B. R.
- Affiliations
- Cornell University (US)
- Corresponding author
- Crane, Brian R.
- Venue
- Nature
- Publisher
- openRxiv
- Published
- 2022-07-27
- Volume
- 617
- Issue
- 7959
- Pages
- 194-199
- ISSN
- 0028-0836 (ISSN-L)
- PMC
- PMC11034853
- OpenAlex
- W4367049164
- Cited by
- 51
- References
- 1
- Citations by year
- 2026: 14 · 2025: 26 · 2024: 9 · 2023: 2
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation (1719875)
- National Institutes of Health (DMR-1719875, 1s10od017992-01)
- Cornell Center for Materials Research (DMR‐1719875, 1719875)
- National Institute of General Medical Sciences (R35GM122535)
- Division of Materials Research (DMR-1719875, 1719875)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- cryptochrome, TIMELESS, circadian clock, Drosophila, armadillo repeats, optical sensing, period, nuclear import, importin alpha, clock period, transcriptional repressor
- MeSH terms
- Animals, Circadian Rhythm, Drosophila melanogaster, Eye Proteins, Light, Mammals, Cryoelectron Microscopy, Active Transport, Cell Nucleus, alpha Karyopherins, Drosophila Proteins, Cryptochromes, Period Circadian Proteins, Circadian Clocks
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