User:Linnea Saunders/Sandbox 1
From Proteopedia
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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. | 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. | + | 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 the transcriptional activity of these genes is increased, cell growth is stimulated, and more cells are promoted to the S phase of the cell cycle. |
== 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, which interact with the PAS domains of the other subunit to maintain the structure of the complex. | + | The main domains of interest within the CLOCK:BMAL1 complex are the Per-Arnt-Sim <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. |
| - | + | PAS domains are present in a large variety of proteins, and their function is often to sense different stimuli, such as oxygen tension, redox potential, and light intensity, but they can also serve to facilitate protein-protein interaction, as is the case of CLOCkBMAL1.<sup>5</sup> The amino acid sequence of this domain varies greatly among the proteins it is present in, as well as among different species, but the structure retains similarities. All PAS domains retain a structure similar to <scene name='84/842915/Photoactive_yellow_protein/1'>photoactive yellow protein</scene>. By clicking through the <scene name='84/842915/Pas_domains_of_clock_bmal1/1'>four PAS domains</scene> of CLOCK:BMAL1, <scene name='84/842915/Pas_domain_1/1'>1</scene>, <scene name='84/842915/Pas_domain_2/1'>2</scene>, <scene name='84/842915/Pas_domain_3/1'>3</scene> and <scene name='84/842915/Pas_domain_4/1'>4</scene>, you can observe the general structural trends of the PAS domain. | |
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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 | ||
| + | 5. 1. Vreede J, Van der Horst MA, Hellingwerf KJ, Crielaard W, Van Aalten DMF. PAS domains. Common structure and common flexibility. J Biol Chem. 2003;278(20):18434-18439. doi:10.1074/jbc.M301701200 | ||
Revision as of 20:47, 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 5. 1. Vreede J, Van der Horst MA, Hellingwerf KJ, Crielaard W, Van Aalten DMF. PAS domains. Common structure and common flexibility. J Biol Chem. 2003;278(20):18434-18439. doi:10.1074/jbc.M301701200
