8dd7 | pdb_00008dd7
The Cryo-EM structure of Drosophila Cryptochrome in complex with Timeless
Structural highlights
FunctionCRY1_DROME Blue light-dependent regulator that is the input of the circadian feedback loop. Has no photolyase activity for cyclobutane pyrimidine dimers or 6-4 photoproducts. Regulation of expression by light suggests a role in photoreception for locomotor activity rhythms. Functions, together with per, as a transcriptional repressor required for the oscillation of peripheral circadian clocks and for the correct specification of clock cells. Genes directly activated by the transcription factors Clock (Clk) and cycle (cyc) are repressed by cry. Necessary for light-dependent magnetosensitivity, an intact circadian system is not required for the magnetoreception mechanism to operate. Required for both the naive and trained responses to magnetic field, consistent with the notion that cry is in the input pathway of magnetic sensing.[1] [2] [3] [4] [5] [6] [7] [8] [9] E5BBQ0_HUMAN Publication Abstract from PubMedCircadian rhythms influence many behaviours 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). Here, through cryogenic electron microscopy of the Cry-Tim complex, we show how a light-sensing cryptochrome recognizes its target. Cry engages a continuous core of amino-terminal Tim armadillo repeats, resembling how photolyases recognize damaged DNA, and binds a C-terminal Tim helix, reminiscent of the interactions between light-insensitive cryptochromes 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-alpha and the nuclear import of Tim-Per(4,5). Moreover, the structure reveals that the N terminus of Tim inserts into the restructured Cry pocket to replace the autoinhibitory C-terminal tail released by light, thereby providing a possible explanation for how the long-short Tim polymorphism adapts flies to different climates(6,7). Cryptochrome-Timeless structure reveals circadian clock timing mechanisms.,Lin C, Feng S, DeOliveira CC, Crane BR Nature. 2023 May;617(7959):194-199. doi: 10.1038/s41586-023-06009-4. Epub 2023 , Apr 26. PMID:37100907[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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