Sandbox Reserved 973: Difference between revisions

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== Effects on the circadian cycle==

Interaction with Per,Cry genes but also PER and CRY proteins is a central mechanism in the circadian cycle regulation ~~as 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 ~~postive~~ charge of CRY also ~~suggest~~ 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 BMAL1 through this interface. One of the clues is the presence of a tryptophane residue which is very conserved in the 2 types of ~~peptides~~.The BMAL1 Trp427 is also present in PER where it mediates the formation of an ~~homodimere~~. 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 BMAL1 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.

But this molecular clock is also regulated by post-translational modifications of the subunits, notably phosphorylation and ubiquitination. Some ~~modifiers~~ proteins can change the stabibility or influence the translocation of some core clock actors, including BMAL1 and CLOCK. That's the case of 2 types of Casein kinase 1 (CK1). Mutations in these modifiers can shorten the circadian cycle of the ~~mamals~~ 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 BMAL1 and CLOCK. 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.

Mutagenesis experiments showed that BMAL1 is normally in excess of CLOCK, which imply that CLOCK is the limiting factor for the dimerization. Indeed, an overexpression of Clock will make the cycle shorter, whereas an overexpression of Bmal1 may have no effect on the cycle length or make it a little longer.

Nevertheless, ~~recents~~ studies showed that each cell has its autonomy towards the circadian cycle and it is important to notice that the two genes Clock and Bmal1 are not identically expressed in every tissues and that the two proteins don't act the same way in this different cell types. Clock mRNA follows a transcriptional cycle in the peripheric oscillators whereas it is constitutively expressed in the SCN. Futhermore the different ROR proteins which have feedback effects on Bmal1 transcription are expressed in a tissue-specific manner, so BMAL1 has various functions at various moments. Again CLOCK doesn't have the same influence on downstream regulated genes depending on the tissue. For example , CLOCK has a limited impact on the amplitudes of the Rev-erbα mRNA oscillation in the SCN. But Clock−/− mice show a important decrease of the same amplitude in the liver. Thus, it is important to keep in mind that the CLOCK:BMAL1 complex subunits are expressed in tissue-specific patterns and that the heterodimer makes a tissue-specific regulation of the circadian clock,which drive the study of the complex functions very difficult.

Nevertheless, recent studies showed that each cell has its autonomy towards the circadian cycle and it is important to notice that the two genes Clock and Bmal1 are not identically expressed in every tissues, and that the two proteins don't act the same way in this different cell types. Clock mRNA follows a transcriptional cycle in the peripheric oscillators whereas it is constitutively expressed in the SCN. Futhermore the different ROR proteins which have feedback effects on Bmal1 transcription are expressed in a tissue-specific manner, so BMAL1 has various functions at various moments. Again, CLOCK doesn't have the same influence on downstream regulated genes, depending on the tissue. For example, CLOCK has a limited impact on the amplitudes of the Rev-erbα mRNA oscillation in the SCN. But Clock−/− mice show a important decrease of the same amplitude in the liver. Thus, it is important to keep in mind that the CLOCK:BMAL1 complex subunits are expressed in tissue-specific patterns and that the heterodimer makes a tissue-specific regulation of the circadian clock, which drive the study of the complex functions very difficult.

== Diseases ==

As we mentionned it above, several mutations of the complex can alter the circadian rhythm. These ~~mutation~~ can affect the structure of the heterodimer and its ability to bind DNA, endanger its stability or modify the interactions with co-regulator clock elements. However, many of them are responsible for numerous pathologies as they have an impact on the whole clock system, involved in different functions, depending on the tissue type. In ~~mamals~~, an increasing number of disorders are thought to be linked with the clock proteins dysfunction. For the single CLOCK:BMAL1 complex, mutations are related to various troubles such as infertility, progressive arthropathy, abnormal gluconeogenesis, abnormal lipogenesis or altered sleep pattern. The complex plays a major role in cellular metabolic pathway so it is linked to hepatic steatosis, hyperleptinemia, hyperglycemia and hypoinsulinemia. BMAL1 is also necessary for embryonic fibroblast cells to differenciate into adipocytes. Another unexpected aspect of the heterodimer functions is that it can influence the efficacy of some drugs. For example, muatnts that don't own this complex show a good response to chemotherapy all day long whereas it varies for the wild mice. Moreover, other disrupted genes such as mutated Per or Cry must be taken into account because they also disturb the proper working of the complex, ~~laeding~~ to other disorders.

As we mentionned it above, several mutations of the complex can alter the circadian rhythm. These mutations can affect the structure of the heterodimer and its ability to bind DNA, endanger its stability or modify the interactions with co-regulator clock elements. However, many of them are responsible for numerous pathologies as they have an impact on the whole clock system, involved in different functions, depending on the tissue type. In mammals, an increasing number of disorders are thought to be linked with the clock proteins dysfunction. For the single CLOCK:BMAL1 complex, mutations are related to various troubles such as infertility, progressive arthropathy, abnormal gluconeogenesis, abnormal lipogenesis or altered sleep pattern. The complex plays a major role in cellular metabolic pathway, so it is linked to hepatic steatosis, hyperleptinemia, hyperglycemia and hypoinsulinemia. BMAL1 is also necessary for embryonic fibroblast cells to differenciate into adipocytes. Another unexpected aspect of the heterodimer functions is that it can influence the efficacy of some drugs. For example, muatnts that don't own this complex show a good response to chemotherapy all day long whereas it varies for the wild mice. Moreover, other disrupted genes such as mutated Per or Cry must be taken into account because they also disturb the proper working of the complex, leading to other disorders.

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@@ Line 32: / Line 32: @@
 == Effects on the circadian cycle==
-Interaction with Per,Cry genes but also PER and CRY proteins is a central mechanism in the circadian cycle regulation as 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 postive charge of CRY also suggest 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 BMAL1 through this interface. One of the clues is the presence of a tryptophane residue which is very conserved in the 2 types of peptides.The BMAL1 Trp427 is also present in PER where it mediates the formation of an homodimere. 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 BMAL1 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.
-But this molecular clock is also regulated by post-translational modifications of the subunits, notably phosphorylation and ubiquitination. Some modifiers proteins can change the stabibility or influence the translocation of some core clock actors, including BMAL1 and CLOCK. That's the case of 2 types of Casein kinase 1 (CK1). Mutations in these modifiers can shorten the circadian cycle of the mamals 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 BMAL1 and CLOCK. 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.
 Mutagenesis experiments showed that BMAL1 is normally in excess of CLOCK, which imply that CLOCK is the limiting factor for the dimerization. Indeed, an overexpression of Clock will make the cycle shorter, whereas an overexpression of Bmal1 may have no effect on the cycle length or make it a little longer.
-Nevertheless, recents studies showed that each cell has its autonomy towards the circadian cycle and it is important to notice that the two genes Clock and Bmal1 are not identically expressed in every tissues and that the two proteins don't act the same way in this different cell types. Clock mRNA follows a transcriptional cycle in the peripheric oscillators whereas it is constitutively expressed in the SCN. Futhermore the different ROR proteins which have feedback effects on Bmal1 transcription are expressed in a tissue-specific manner, so BMAL1 has various functions at various moments. Again CLOCK doesn't have the same influence on downstream regulated genes depending on the tissue. For example , CLOCK has a limited impact on the amplitudes of the Rev-erbα mRNA oscillation in the SCN. But Clock−/− mice show a important decrease of the same amplitude in the liver. Thus, it is important to keep in mind that the CLOCK:BMAL1 complex subunits are expressed in tissue-specific patterns and that the heterodimer makes a tissue-specific regulation of the circadian clock,which drive the study of the complex functions very difficult.
+Nevertheless, recent studies showed that each cell has its autonomy towards the circadian cycle and it is important to notice that the two genes Clock and Bmal1 are not identically expressed in every tissues, and that the two proteins don't act the same way in this different cell types. Clock mRNA follows a transcriptional cycle in the peripheric oscillators whereas it is constitutively expressed in the SCN. Futhermore the different ROR proteins which have feedback effects on Bmal1 transcription are expressed in a tissue-specific manner, so BMAL1 has various functions at various moments. Again, CLOCK doesn't have the same influence on downstream regulated genes, depending on the tissue. For example, CLOCK has a limited impact on the amplitudes of the Rev-erbα mRNA oscillation in the SCN. But Clock−/− mice show a important decrease of the same amplitude in the liver. Thus, it is important to keep in mind that the CLOCK:BMAL1 complex subunits are expressed in tissue-specific patterns and that the heterodimer makes a tissue-specific regulation of the circadian clock, which drive the study of the complex functions very difficult.
 == Diseases ==
-As we mentionned it above, several mutations of the complex can alter the circadian rhythm. These mutation can affect the structure of the heterodimer and its ability to bind DNA, endanger its stability or modify the interactions with co-regulator clock elements. However, many of them are responsible for numerous pathologies as they have an impact on the whole clock system, involved in different functions, depending on the tissue type. In mamals, an increasing number of disorders are thought to be linked with the clock proteins dysfunction. For the single CLOCK:BMAL1 complex, mutations are related to various troubles such as infertility, progressive arthropathy, abnormal gluconeogenesis, abnormal lipogenesis or altered sleep pattern. The complex plays a major role in cellular metabolic pathway so it is linked to hepatic steatosis, hyperleptinemia, hyperglycemia and hypoinsulinemia. BMAL1 is also necessary for embryonic fibroblast cells to differenciate into adipocytes. Another unexpected aspect of the heterodimer functions is that it can influence the efficacy of some drugs. For example, muatnts that don't own this complex show a good response to chemotherapy all day long whereas it varies for the wild mice. Moreover, other disrupted genes such as mutated Per or Cry must be taken into account because they also disturb the proper working of the complex, laeding to other disorders.
+As we mentionned it above, several mutations of the complex can alter the circadian rhythm. These mutations can affect the structure of the heterodimer and its ability to bind DNA, endanger its stability or modify the interactions with co-regulator clock elements. However, many of them are responsible for numerous pathologies as they have an impact on the whole clock system, involved in different functions, depending on the tissue type. In mammals, an increasing number of disorders are thought to be linked with the clock proteins dysfunction. For the single CLOCK:BMAL1 complex, mutations are related to various troubles such as infertility, progressive arthropathy, abnormal gluconeogenesis, abnormal lipogenesis or altered sleep pattern. The complex plays a major role in cellular metabolic pathway, so it is linked to hepatic steatosis, hyperleptinemia, hyperglycemia and hypoinsulinemia. BMAL1 is also necessary for embryonic fibroblast cells to differenciate into adipocytes. Another unexpected aspect of the heterodimer functions is that it can influence the efficacy of some drugs. For example, muatnts that don't own this complex show a good response to chemotherapy all day long whereas it varies for the wild mice. Moreover, other disrupted genes such as mutated Per or Cry must be taken into account because they also disturb the proper working of the complex, leading to other disorders.