8DD7

The Cryo-EM structure of Drosophila Cryptochrome in complex with Timeless

Summary for 8DD7

• Entry DOI: 10.2210/pdb8dd7/pdb
• EMDB information: 27335
• Descriptor: Methylated-DNA--protein-cysteine methyltransferase,Cryptochrome-1 fusion, Protein timeless,Methylated-DNA--protein-cysteine methyltransferase fusion, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: flavoprotein, nuclear import, light-sensor, armadillo-repeat protein, circadian clock protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 264620.28

Authors

Feng, S.,Lin, C.,DeOliveira, C.C.,Crane, B.R. (deposition date: 2022-06-17, release date: 2023-02-15, Last modification date: 2024-06-12)

Primary citation

Lin, C.,Feng, S.,DeOliveira, C.C.,Crane, B.R.
Cryptochrome-Timeless structure reveals circadian clock timing mechanisms.
Nature, 617:194-199, 2023

PubMed Abstract: Circadian rhythms influence many behaviours and diseases. 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. 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-α and the nuclear import of Tim-Per. 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.

PubMed: 37100907
DOI: 10.1038/s41586-023-06009-4

Experimental method

ELECTRON MICROSCOPY (3.3 Å)