User:Linnea Saunders/Sandbox 1
From Proteopedia
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'''Linnea Saunders/Sandbox 1 '''CLOCK:BMAL1 Transcriptional Activator Complex'''''' | '''Linnea Saunders/Sandbox 1 '''CLOCK:BMAL1 Transcriptional Activator Complex'''''' | ||
| - | == | + | == Overview == |
| - | The circadian locomotor output cycles protein kaput and brain-muscle-arnt-like (CLOCK:BMAL1) transcriptional activator complex is an important protein involved in the regulation of our circadian rhythm. This protein is a heterodimer of CLOCK and BMAL1. Its main function is to interact with DNA at regulatory elements to upregulate the production of proteins period (PER) and cryptochrome (CRY) during the day. These proteins (PER and CRY) heterodimerize at night and interact with CLOCK:BMAL1 to repress the transcription of PER and CRY.<sup>1</sup> They are then degraded, allowing their transcription to occur again. This process takes approximately 24 hours and is the main mechanism of the circadian rhythm, and CLOCK:BMAL1 lies at the heart of this process.<sup>2</sup> In addition to regulating PER and CRY, CLOCK:BMAL1 regulates the transcription of ''Rev-erbα'', which is a nuclear hormone receptor).<sup>3</sup> ''Rev-erbα'' once transcribed, inhibits the transcription of BMAL1. | + | The circadian locomotor output cycles protein kaput and brain-muscle-arnt-like (CLOCK:BMAL1) transcriptional activator complex is an important protein involved in the regulation of our circadian rhythm. The protein shown at the right is a crystallized structure of this complex from ''Mus musculus''. This protein is a heterodimer of CLOCK and BMAL1. Its main function is to interact with DNA at regulatory elements to upregulate the production of proteins period (PER) and cryptochrome (CRY) during the day. These proteins (PER and CRY) heterodimerize at night and interact with CLOCK:BMAL1 to repress the transcription of PER and CRY.<sup>1</sup> They are then degraded, allowing their transcription to occur again. This process takes approximately 24 hours and is the main mechanism of the circadian rhythm, and CLOCK:BMAL1 lies at the heart of this process.<sup>2</sup> |
| - | CLOCK:BMAL1 contains two necessary domain structures to facilitate its function in the cell, as well as sites for phosphorylation, acetylation, O-glycosylation, sumoylation and ubiquitination, which allow for dimerization, increasing transcriptional activity, and degradation of the complex. | + | In addition to regulating PER and CRY, CLOCK:BMAL1 regulates the transcription of ''Rev-erbα'', which is a nuclear hormone receptor).<sup>3</sup> ''Rev-erbα'' once transcribed, inhibits the transcription of BMAL1. |
| + | CLOCK:BMAL1 contains two necessary domain structures to facilitate its function in the cell, as well as sites for phosphorylation, acetylation, O-glycosylation, sumoylation, and ubiquitination, which allow for dimerization, increasing transcriptional activity, and degradation of the complex. | ||
== Disease == | == Disease == | ||
| - | + | CLOCK:BMAL1 is known to be a factor in hormone-related breast cancer by contributing to cell growth. Estrogen receptor-α (ERα), when stimulated by estrogen, interacts with CLOCK to increase transcriptional activity at genes regulated by CLOCK:BMAL1. This is achieved by promoting sumoylation of CLOCK at <scene name='84/842915/Sumoylation_site/1'>residue K67</scene>.<sup>4</sup> When transcriptional activity of these genes is increased, cell growth is stimulated, and more cells are promoted to the S phase of the cell cycle. | |
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== Structural highlights == | == Structural highlights == | ||
| - | The main domains of interest within the CLOCK:BMAL1 complex are the <scene name='84/842915/Pas_domains/1'>PAS domains</scene>, which are necessary for dimerization, and the <scene name='84/842915/Bhlh_1/1'>basic Helix Loop Helix (bHLH) domains</scene>, which allows the complex to interact with DNA. Each subunit contains two PAS domains | + | The main domains of interest within the CLOCK:BMAL1 complex are the <scene name='84/842915/Pas_domains/1'>PAS domains</scene>, which are necessary for dimerization, and the <scene name='84/842915/Bhlh_1/1'>basic Helix Loop Helix (bHLH) domains</scene>, which allows the complex to interact with DNA. Each subunit contains two PAS domains, which interact with the PAS domains of the other subunit to maintain the structure of the complex. |
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== References == | == References == | ||
1. 1. Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2013;32(41):4883-4891. doi:10.1038/onc.2012.518 | 1. 1. Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2013;32(41):4883-4891. doi:10.1038/onc.2012.518 | ||
| - | 2.Menet JS, Pescatore S, Rosbash M. CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev. 2014;28(1):8–13. doi:10.1101/gad.228536.113 | + | 2. Menet JS, Pescatore S, Rosbash M. CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev. 2014;28(1):8–13. doi:10.1101/gad.228536.113 |
<references/> | <references/> | ||
3. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008;9(10):764–775. doi:10.1038/nrg2430 | 3. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008;9(10):764–775. doi:10.1038/nrg2430 | ||
4. 1. Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2013;32(41):4883-4891. doi:10.1038/onc.2012.518 | 4. 1. Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2013;32(41):4883-4891. doi:10.1038/onc.2012.518 | ||
Revision as of 20:10, 26 April 2020
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References
1. 1. Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2013;32(41):4883-4891. doi:10.1038/onc.2012.518 2. Menet JS, Pescatore S, Rosbash M. CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev. 2014;28(1):8–13. doi:10.1101/gad.228536.113
3. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 2008;9(10):764–775. doi:10.1038/nrg2430 4. 1. Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2013;32(41):4883-4891. doi:10.1038/onc.2012.518
