Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK

Langmesser, Sonja; Tallone, Tiziano; Bordon, Alain; Rusconi, Sandro; Albrecht, Urs

doi:10.1186/1471-2199-9-41

Cited by 112 publications

(90 citation statements)

References 37 publications

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“…As a negative control we examined the ability of each ID protein to interact with the clock protein CRY1, which does not possess an HLH domain. As predicted, no interaction was detected between ID proteins and CRY1, but consistent with other studies, we detected an interaction between BMAL1 and CRY1 (46). It is important to note that the ID2-GAL4-CLOCK-VP16 and ID2-GAL4-BMAL1-VP16 interactions were in the range of 42-86% as robust as the established CLOCK-BMAL1 interaction.…”

Section: Discussionsupporting

confidence: 75%

“…B-D, NIH3T3 cells were co-transfected with pGL5-Luc, ␤-gal, and the indicated expression plasmids. Shown are positive controls of known robustly interacting binding partners, CLOCK and BMAL1 (34,46) and ID1 and MyoD (60) (B) and testing ID2 interaction with CLOCK and BMAL1 (C). D, as a negative control, the ability for ID2 to interact with CRY1 was tested, and a positive interaction signal was observed for BMAL1 with CRY1 (46).…”

Section: Id2 Can Interact With Both Clock and Bmal1 Complexes-mentioning

confidence: 99%

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The Transcriptional Repressor ID2 Can Interact with the Canonical Clock Components CLOCK and BMAL1 and Mediate Inhibitory Effects on mPer1 Expression

Ward

Fernando

Hou

et al. 2010

Journal of Biological Chemistry

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Circadian rhythms are 24-h temporal patterns of biochemistry, physiology, and behavior that are an integral component of eukaryotic life (1, 2). The molecular circadian clock is a cell autonomous system composed of three conceptual components: a self-sustainable pacemaker that generates 24-h rhythmicity; an input pathway that allows the clock to be reset and entrained by temporal cues in the environment; and mechanisms of output that regulate molecular and biochemical pathways and ultimately translate to rhythms in physiology and behavior. The master circadian pacemaker resides in the suprachiasmatic nucleus (SCN) 2 of the hypothalamus (1). Additionally, peripheral tissues and cell lines contain self-sustaining clocks (3-6). The molecular clock is comprised of a series of transcriptional-translational feedback loops that take ϳ24 h to complete. The positive loop contains the basic helix-loop-helix (bHLH)/PAS (Per-Arnt-Sim) proteins BMAL1 (brain and muscle ARNT-like 1) and CLOCK (Circadian locomotor output cycle kaput) and/or NPAS2 (neuronal PAS domain-containing protein 2). These transcription factors interact through their PAS and HLH regions and bind to the promoter region of their target genes of the negative loop at specific E-box regulatory elements (CACGTG), resulting in transcriptional activation. The negative loop is comprised of the period (mPer1, mPer2, mPer3) and cryptochrome genes (mCry1, mCry2). Rev-ERB␣ and ROR␣ are additional components that close the interlocking loops, and additional loops have been identified (e.g. Dec1, Dec2), which are proposed to increase stability and precision of the clock (1, 2, 7-9).The clock is reset by Zeitgeber stimuli through input pathways that transiently induce or suppress levels of period gene transcripts (1, 2, 10, 11). In the case of the SCN, light activation of retinal photoreceptors and the retinal hypothalamic tract results in stimulation of SCN neurons. Activation of several intracellular signaling pathways culminates in the phosphorylation of Ca 2ϩ /cAMP response element binding protein (CREB) (12-15). Phospho-CREB (pCREB) can then bind to its response element, the CRE, within the promoter region of target genes, such as the immediate early gene c-fos and immediate early gene/clock genes mPer1 and mPer2. Phase shifts of the SCN clock by elements of the photic signaling pathways results in elevation of mPer1 (and sometimes mPer2). Nonphotic (arousal) generated phase shifts result in suppression of mPer1 (1, 11). Furthermore, phase shifts of clocks in peripheral tissues and cell lines by serum, hormone, and nutrient signaling elicit * This work was supported, in whole or in part, by NIGMS, National Institutes of Health Grant GM087508 (to G. E. D.

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Section: Discussionsupporting

confidence: 75%

Section: Id2 Can Interact With Both Clock and Bmal1 Complexes-mentioning

confidence: 99%

The Transcriptional Repressor ID2 Can Interact with the Canonical Clock Components CLOCK and BMAL1 and Mediate Inhibitory Effects on mPer1 Expression

Ward

Fernando

Hou

et al. 2010

Journal of Biological Chemistry

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“…6), and the amount of precipitated BMAL2b was significantly higher than that of BMAL1 and comparable with that of BMAL2a. This observation falls into line with the previous finding by Langmesser et al (43) that PER2 can interact with a truncated form of BMAL1 (amino acids 1-278 of mBMAL1b isoform) lacking the C-terminal half (including PAS-B domain). Consistently, the bHLH and PAS-A domains of BMAL2 share 60 and 73% amino acid identities with those of BMAL1, respectively.…”

Section: Bmal2 Is Less Sensitive Than Bmal1 To Repression By Crys Butsupporting

confidence: 81%

“…Physical Interaction of PER2 with BMAL2 Is Stronger than That with BMAL1-PER2 is known to interact with BMAL1 (42,43), whereas the intimate functional linkage between PER2 and BMAL2 (Fig. 5) suggested that PER2 may associate with BMAL2 more efficiently than with BMAL1.…”

Section: Bmal2 Is Less Sensitive Than Bmal1 To Repression By Crys Butmentioning

confidence: 95%

Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

Sasaki

Yoshitane

et al. 2009

Journal of Biological Chemistry

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In the molecular oscillatory mechanism governing circadian rhythms, positive regulators, including CLOCK and BMAL1, transactivate Per and Cry genes through E-box elements, and translated PER and CRY proteins negatively regulate their own transactivation. Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription, but the role of BMAL2 in the circadian clockwork is still elusive. Here we characterized BMAL2 function in NIH3T3 cells and found that the cellular rhythms monitored by Bmal1 promoterdriven bioluminescence signals were blunted by RNA interference-mediated suppression of Bmal2 as well as that of Bmal1. Transcription assays with a 2.1-kb mPer1 promoter revealed that CRY2 inhibited the transactivation mediated by BMAL1-CLOCK more strongly than that by BMAL2-CLOCK. In contrast, PER2 showed a stronger inhibitory effect on BMAL2-CLOCK than on BMAL1-CLOCK. The molecular link between BMAL2 and PER2 was further strengthened by the fact that PER2 exhibited a greater affinity for BMAL2 than for BMAL1 in co-immunoprecipitation experiments. These results indicate a functional partnership between BMAL2 and PER2 and reemphasize the negative role of PER2 in the circadian transcription. As a broad spectrum function, BMAL2-CLOCK activated transcription from a variety of SV40-driven reporters harboring various E/E-box-containing sequences present in the upstream regions of clock and clock-controlled genes. Importantly, the efficiencies of BMAL2-CLOCK-mediated transactivation relative to that achieved by BMAL1-CLOCK were dependent heavily on the E-box-containing sequences, supporting distinguishable roles of the two BMALs. Collectively, it is strongly suggested that BMAL2 plays an active role in the circadian transcription.A variety of organisms from bacteria to humans show circadian rhythms in physiology and behavior under the regulation of endogenous circadian clocks oscillating with an ϳ24-h periodicity (1, 2). In mammals, the central clock is located in the hypothalamic suprachiasmatic nucleus, whereas peripheral clocks with self-sustainable oscillation machinery are located in many peripheral tissues (3). Even cultured fibroblasts were shown to retain the cellular clocks (4), and hence they have been used for studies on the oscillatory mechanism of peripheral clocks. The molecular clockwork in mammals centers on transcription/translation-based autoregulatory feedback loops of clock genes, to which bHLH 3 -PAS proteins, BMAL1 and CLOCK, contribute as positive regulators of the transcription (2, 5). BMAL1-CLOCK complex activates transcription through CACGTG-type E-box and its related sequences found in promoter regions of clock genes and clock-controlled genes such as Per1 (6), Per2 (CACGTT E-box-like or EЈ-box sequence; see Ref. 7), plasminogen activator inhibitor-1 (PAI-1) (8), and Rev-Erb␣/␤ (9, 10). The E-box-dependent transactivation mediated by the BMAL1-CLOCK complex is suppressed by an expanding number of negative regulators, including PER1 (11, 12), PER2 (13-15), PER3 (16,1...

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“…The PAS domains mediate homo-and heterodimeric interactions between the mPER homologues (5)(6)(7)(8) as well as interactions of the mPERs with mBMAL1/2, mCLOCK, and NPAS2 (9)(10)(11)(12). These interactions regulate the stability and cellular localization of the mPERs and modulate the activity of the mBMAL1/mCLOCK transcription factor complex.…”

mentioning

confidence: 99%

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

Kucera

Schmalen

Hennig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The three PERIOD homologues mPER1, mPER2, and mPER3 constitute central components of the mammalian circadian clock. They contain two PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B), which mediate homo-and heterodimeric mPER-mPER interactions as well as interactions with transcription factors and kinases. Here we present crystal structures of PAS domain fragments of mPER1 and mPER3 and compare them with the previously reported mPER2 structure. The structures reveal homodimers, which are mediated by interactions of the PAS-B β-sheet surface including a highly conserved tryptophan (Trp448 mPER1 , Trp419 mPER2 , Trp359 mPER3 ). mPER1 homodimers are additionally stabilized by interactions between the PAS-A domains and mPER3 homodimers by an N-terminal region including a predicted helix-loop-helix motive. We have verified the existence of these homodimer interfaces in solution and inside cells using analytical gel filtration and luciferase complementation assays and quantified their contributions to homodimer stability by analytical ultracentrifugation. We also show by fluorescence recovery after photobleaching analyses that destabilization of the PAS-B/tryptophan dimer interface leads to a faster mobility of mPER2 containing complexes in human U2OS cells. Our study reveals structural and quantitative differences between the homodimeric interactions of the three mouse PERIOD homologues, which are likely to contribute to their distinct clock functions.circadian clock | PAS domains | PERIOD proteins | protein interactions

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Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK

Cited by 112 publications

References 37 publications

The Transcriptional Repressor ID2 Can Interact with the Canonical Clock Components CLOCK and BMAL1 and Mediate Inhibitory Effects on mPer1 Expression

The Transcriptional Repressor ID2 Can Interact with the Canonical Clock Components CLOCK and BMAL1 and Mediate Inhibitory Effects on mPer1 Expression

Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

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