Sandbox Reserved 973: Difference between revisions

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Interaction with Per and Cry genes, but also PER and CRY proteins is a central mechanism in the circadian cycle regulation. The downstream products PER and CRY can then accumulate and dimerize too, so they can repress transcription of Bmal1 and Clock at night, after they relocated in the cell nucleus, creating an autoregulatory feedback loop. These interactions are not completly elucitaded yet but some cristallography and site-directed mutagenesis experiments brought some new elements. CRY and PER seem to interact with CLOCK:BMAL1 to form a bigger repression complex but the mechanism of the repression activity is still unknown. CRY proteins are likely to bind on the CLOCK PAS-B domain thanks to the presence of the β-sheet or on the C-terminal region of BMAL1. The global positive charge of CRY also suggests an interaction with the CLOCK PAS domains as it is negatively charged. Mutations of residues Gln332, His360, Gln361, Trp362 and Glu367 of the CLOCK PAS-B domain delay the repression by CRY, which is another argument in favor of this hypothesis. What's more an unexpected similary was found between the BMAL1 PAS domains and the PER proteins PAS domains. This suggests an interaction of PER with <scene name='60/604492/Bmal1/1'>BMAL1</scene> through this interface. One of the clues is the presence of a tryptophane residue which is very conserved in the 2 types of polypeptides. The BMAL1 Trp427 is also present in PER where it mediates the formation of an homodimer. It may be a key residue for the binding of PER.  
Interaction with Per and Cry genes, but also PER and CRY proteins is a central mechanism in the circadian cycle regulation. The downstream products PER and CRY can then accumulate and dimerize too, so they can repress transcription of Bmal1 and Clock at night, after they relocated in the cell nucleus, creating an autoregulatory feedback loop. These interactions are not completly elucitaded yet but some cristallography and site-directed mutagenesis experiments brought some new elements. CRY and PER seem to interact with CLOCK:BMAL1 to form a bigger repression complex but the mechanism of the repression activity is still unknown. CRY proteins are likely to bind on the CLOCK PAS-B domain thanks to the presence of the β-sheet or on the C-terminal region of BMAL1. The global positive charge of CRY also suggests an interaction with the CLOCK PAS domains as it is negatively charged. Mutations of residues Gln332, His360, Gln361, Trp362 and Glu367 of the CLOCK PAS-B domain delay the repression by CRY, which is another argument in favor of this hypothesis. What's more an unexpected similary was found between the BMAL1 PAS domains and the PER proteins PAS domains. This suggests an interaction of PER with <scene name='60/604492/Bmal1/1'>BMAL1</scene> through this interface. One of the clues is the presence of a tryptophane residue which is very conserved in the 2 types of polypeptides. The BMAL1 Trp427 is also present in PER where it mediates the formation of an homodimer. It may be a key residue for the binding of PER.  


On the other hand, CLOCK:BMAL 1 is also able to activate the transcription of retinoic acid-related nuclear receptors: Rev-erbα and Rorα.These proteins have the ability to regulate the transcription of Bmal1, RORα as an activator and REV-ERBα as a repressor.
On the other hand, CLOCK:BMAL 1 is also able to activate the transcription of retinoic acid-related nuclear receptors<ref>10.1093/hmg/ddl207</ref>: Rev-erbα and Rorα.These proteins have the ability to regulate the transcription of Bmal1, RORα as an activator and REV-ERBα as a repressor.
But this molecular clock is also regulated by post-translational modifications of the subunits, notably phosphorylation and ubiquitination. Some modifier proteins can change the stabibility or influence the translocation of some core clock actors, including <scene name='60/604492/Bmal1/1'>BMAL1</scene> and <scene name='60/604492/Clock/1'>CLOCK</scene>. That is the case of 2 types of Casein kinase 1 (CK1). Mutations in these modifiers can shorten the circadian cycle of the mammals and cause serious sleep disorders.
But this molecular clock is also regulated by post-translational modifications of the subunits, notably phosphorylation and ubiquitination. Some modifier proteins can change the stabibility or influence the translocation of some core clock actors, including <scene name='60/604492/Bmal1/1'>BMAL1</scene> and <scene name='60/604492/Clock/1'>CLOCK</scene>. That is the case of 2 types of Casein kinase 1 (CK1). Mutations in these modifiers can shorten the circadian cycle of the mammals and cause serious sleep disorders.


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