The tail of cryptochromes: an intrinsically disordered cog within the mammalian circadian clock

Parico, Gian Carlo G; Partch, Carrie L.

doi:10.1186/s12964-020-00665-z

Cited by 26 publications

(22 citation statements)

References 59 publications

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“…Furthermore, several differentiation-associated transcription factor families exhibit a strong correlation between increasing fractions of predicted disorder and increasing organism complexity as estimated by numbers of different cell types [ 51 ], suggesting that increased organism complexity requires increased transcription factor complexity to handle the increasing complexity of the gene regulation. Also, the expressed proteins resulting from the gene regulation and underlying cellular differentiation of both plants and animals show a high occurrence of predicted disorder [ 52 – 57 ].…”

Section: Global Analysis Of Protein Functionmentioning

confidence: 99%

“…Clock proteins utilize intrinsic disorder for post translational modifications, protein–protein interactions, and complex regulation, thereby indicating that conserved intrinsic disorder is essential for optimal circadian timing. Parico and Partch [ 57 ] continue discussion of the roles of intrinsic disorder in controling and regulation of circadian rhythms by describing the involvement of intrinsically disordered C-terminal tail in functionality of the cryptochromes (CRYs), which are blue light sensitive flavoproteins involved in the circadian rhythms and magnetic field sensing. CRY contains two functional domains, ordered N-terminal photolyase homology region (PHR) and intrinsically disordered C-terminal domain.…”

Section: The Idp/idr In Signaling Collectionmentioning

confidence: 99%

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On the roles of intrinsically disordered proteins and regions in cell communication and signaling

2021

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For proteins, the sequence → structure → function paradigm applies primarily to enzymes, transmembrane proteins, and signaling domains. This paradigm is not universal, but rather, in addition to structured proteins, intrinsically disordered proteins and regions (IDPs and IDRs) also carry out crucial biological functions. For these proteins, the sequence → IDP/IDR ensemble → function paradigm applies primarily to signaling and regulatory proteins and regions. Often, in order to carry out function, IDPs or IDRs cooperatively interact, either intra- or inter-molecularly, with structured proteins or other IDPs or intermolecularly with nucleic acids. In this IDP/IDR thematic collection published in Cell Communication and Signaling, thirteen articles are presented that describe IDP/IDR signaling molecules from a variety of organisms from humans to fruit flies and tardigrades (“water bears”) and that describe how these proteins and regions contribute to the function and regulation of cell signaling. Collectively, these papers exhibit the diverse roles of disorder in responding to a wide range of signals as to orchestrate an array of organismal processes. They also show that disorder contributes to signaling in a broad spectrum of species, ranging from micro-organisms to plants and animals.

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Section: Global Analysis Of Protein Functionmentioning

confidence: 99%

Section: The Idp/idr In Signaling Collectionmentioning

confidence: 99%

On the roles of intrinsically disordered proteins and regions in cell communication and signaling

2021

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“…The length of the C-terminal tail (CTT) extension (Fig. 1A) is variable, ranging from 20 residues in insects to about 200 residues in plants, regulating signaling propagation and specific functions (3,5). The CRY in Drosophila (dCRY) is the primary circadian photoreceptor, and excitation of the flavin chromophore triggers dCRY conformational change, following dissociation of the 20-amino acid CTT from the PHR binding pocket (6,7).…”

Section: Introductionmentioning

confidence: 99%

Activation mechanism of Drosophila cryptochrome through an allosteric switch

et al. 2021

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Cryptochromes are signaling proteins activated by photoexcitation of the flavin adenine dinucleotide (FAD) cofactor. Although extensive research has been performed, the mechanism for this allosteric process is still unknown. We constructed three computational models, corresponding to different redox states of the FAD cofactor in Drosophila cryptochrome (dCRY). Analyses of the dynamics trajectories reveal that the activation process occurs in the semiquinone state FAD−●, resulting from excited-state electron transfer. The Arg381-Asp410 salt bridge acts as an allosteric switch, regulated by the change in the redox state of FAD. In turn, Asp410 forms new hydrogen bonds, connecting allosteric networks of the amino-terminal and carboxyl-terminal domains initially separated in the resting state. The expansion to a global dynamic network leads to enhanced protein fluctuations, an increase in the radius of gyration, and the expulsion of the carboxyl-terminal tail. These structural features are in accord with mutations and spectroscopic experiments.

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“…Overall, our data indicates 1) that TIM binding requires CTT undocking and the distribution of docked and undocked conformations correlate with TIM affinity; 2) flavin reduction is required for CTT undocking and the resulting enhancement of TIM binding is of reasonable magnitude to regulate the system; 3) the undocking mechanism is sensitive to the 377 and 378 residues, with the highest fidelity switching requiring His at both positions and 4) TIM very likely interfaces with the pocket exposed by CTT undocking. The general role of CCE in gating and modulating the interactions of different CRY proteins with both targets and small molecules is well established and has been recently discussed in detail Crane, 2020;Miller et al, 2020b;a;Miller et al, 2020c;Parico and Partch, 2020). Although in many cases the molecular details remain to be worked out, the root of the sensing mechanisms involve light-or ligandinduced shifts in equilibria of docked and undocked CCEs, which thereby control binding to CRY interactors.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insight into light-dependent recognition of Timeless by Drosophila cryptochrome

Lin

Schneps

Chandrasekaran

et al. 2021

Preprint

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Cryptochrome (CRY) entrains the fly circadian clock by binding to Timeless (TIM) in light and triggering its degradation. Undocking of a helical C-terminal tail (CTT) in response to photoreduction of the CRY flavin cofactor gates TIM binding. A generally-applicable Select Western-blot-Free Tagged-protein Interaction (SWFTI) assay enables quantification of CRY binding to TIM in dark and light. The assay is utilized to study CRY variants with residue substitutions in the flavin pocket and correlate their TIM affinities with CTT undocking, as measured by pulse-dipolar ESR spectroscopy and evaluated by molecular dynamics simulations. CRY variants with the CTT removed or undocked bind TIM constitutively, whereas those incapable of photoreduction bind TIM weakly. In response to flavin redox state, two conserved histidine residues contribute to a robust on/off switch by mediating CTT interactions with the flavin pocket and TIM. Our approach provides an expeditious means to quantify protein-protein interactions and photoreceptor targeting.

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The tail of cryptochromes: an intrinsically disordered cog within the mammalian circadian clock

Cited by 26 publications

References 59 publications

On the roles of intrinsically disordered proteins and regions in cell communication and signaling

On the roles of intrinsically disordered proteins and regions in cell communication and signaling

Activation mechanism of Drosophila cryptochrome through an allosteric switch

Mechanistic insight into light-dependent recognition of Timeless by Drosophila cryptochrome

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