Phosphorylation and nuclear translocation of the CRY:PER:kinase complex

Stable Identifier
R-HSA-9931530
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Phosphorylation and nuclear translocation of the CRY:PER:kinase complex
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Cryptochrome proteins (CRY1, CRY2) and Period proteins (PER1, PER2, PER3) are translated in the cytosol. CDK5 phosphoryates PER2 in the cytosol and phosphorylated PER2 interacts with CRY1 (inferred from mouse homologs in Brenna et al. 2019). The heterodimer associates with kinases Casein kinase I delta (CSNK1D) and Casein kinase I epsilon (CSNK1E) and other CRY and PER proteins in a large complex in the cytosol (inferred from mouse homologs in Nangle et al. 2014, Aryal et al. 2017) and the CRY and PER proteins are phosphorylated by CSNK1D and CSNK1E (Toh et al. 2001, Camacho et al. 2001, inferred from mouse homologs in Akashi et al. 2002, Eide et al. 2002, reviewed in Hirano et al. 2016, Yang et al. 2017, Ode et al. 2018, Narasimamurthy and Virshup 2021). The large complex containing the phosphorylated CRY and PER proteins is then translocated into the nucleus (inferred from mouse homologs in Kume et al. 1999, Vielhaber et al. 2000, Aryal et al. 2017, Cao et al. 2023), though there is a discrepancy in the measured sizes of the nuclear complex. Cao et al. (2023) used gel exclusion chromatography and glycerol gradient centrifugation and found a mass of 707 kDa: Aryal et al. (2017) used a novel electrophoretic method and found a mass of 1.9 MDa. The large CRY:PER:kinase complex then associates with phosphorylated BMAL1:CLOCK heterodimers (and likely with BMAL1:NPAS2 heterodimers) and represses the transactivation activity of BMAL1:CLOCK (inferred from mouse homologs in Griffin et al. 1999, Ye et al. 2014, Chiou et al. 2016, Cao et al. 2021).
Literature References
PubMed ID Title Journal Year
11232563 An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome

Toh, KL, Jones, CR, He, Y, Eide, EJ, Hinz, WA, Virshup, DM, Ptácek, LJ, Fu, YH

Science 2001
28057520 Molecular basis for the regulation of the circadian clock kinases CK1δ and CK1ε

Yang, Y, Xu, T, Zhang, Y, Qin, X

Cell Signal 2017
36682495 Analysis of mammalian circadian clock protein complexes over a circadian cycle

Cao, X, Wang, L, Selby, CP, Lindsey-Boltz, LA, Sancar, A

J Biol Chem 2023
10531061 Light-independent role of CRY1 and CRY2 in the mammalian circadian clock

Griffin EA, Jr, Staknis, D, Weitz, CJ

Science 1999
25127877 Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex

Nangle, SN, Rosensweig, C, Koike, N, Tei, H, Takahashi, JS, Green, CB, Zheng, N

Elife 2014
31687929 Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock

Brenna, A, Olejniczak, I, Chavan, R, Ripperger, JA, Langmesser, S, Cameroni, E, Hu, Z, De Virgilio, C, Dengjel, J, Albrecht, U

Elife 2019
10848614 Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon

Vielhaber, E, Eide, E, Rivers, A, Gao, ZH, Virshup, DM

Mol Cell Biol 2000
25228643 Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock

Ye, R, Selby, CP, Chiou, YY, Ozkan-Dagliyan, I, Gaddameedhi, S, Sancar, A

Genes Dev 2014
29038116 Design Principles of Phosphorylation-Dependent Timekeeping in Eukaryotic Circadian Clocks

Ode, KL, Ueda, HR

Cold Spring Harb Perspect Biol 2018
33443219 Molecular mechanism of the repressive phase of the mammalian circadian clock

Cao, X, Yang, Y, Selby, CP, Liu, Z, Sancar, A

Proc Natl Acad Sci U S A 2021
10428031 mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop

Kume, K, Zylka, MJ, Sriram, S, Shearman, LP, Weaver, DR, Jin, X, Maywood, ES, Hastings, MH, Reppert, SM

Cell 1999
33545069 The phosphorylation switch that regulates ticking of the circadian clock

Narasimamurthy, R, Virshup, DM

Mol Cell 2021
11165242 Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2

Camacho, F, Cilio, M, Guo, Y, Virshup, DM, Patel, K, Khorkova, O, Styren, S, Morse, B, Yao, Z, Keesler, GA

FEBS Lett 2001
27922612 The intricate dance of post-translational modifications in the rhythm of life

Hirano, A, Fu, YH, Ptácek, LJ

Nat Struct Mol Biol 2016
11865049 Control of intracellular dynamics of mammalian period proteins by casein kinase I epsilon (CKIepsilon) and CKIdelta in cultured cells

Akashi, M, Tsuchiya, Y, Yoshino, T, Nishida, E

Mol Cell Biol 2002
11875063 The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon

Eide, EJ, Vielhaber, EL, Hinz, WA, Virshup, DM

J Biol Chem 2002
27688755 Mammalian Period represses and de-represses transcription by displacing CLOCK-BMAL1 from promoters in a Cryptochrome-dependent manner

Chiou, YY, Yang, Y, Rashid, N, Ye, R, Selby, CP, Sancar, A

Proc. Natl. Acad. Sci. U.S.A. 2016
28886335 Macromolecular Assemblies of the Mammalian Circadian Clock

Aryal, RP, Kwak, PB, Tamayo, AG, Gebert, M, Chiu, PL, Walz, T, Weitz, CJ

Mol Cell 2017
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Authored
May, B  (2024-12-09)
Reviewed
Sancar, A  (2025-02-14)
Albrecht, U  (2025-02-18)
Created
May, B  (2024-12-12)
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