Sandbox Reserved 1122: Difference between revisions
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=== IP3R inhibition === | === IP3R inhibition === | ||
Bcl-2 localized at the ER membrane participates in the control of Ca2+ content and release. The inositol 1,4,5-trisphosphate receptor (IP3R) is the Ca2+ release channel localized in the ER. Its pro-apoptotic activity can be directly inhibited by Bcl-2, its homology domain 4 (BH4) being essential for this effect. <scene name='71/719863/Scenelucas/2'>BH4</scene> comprises 20 amino acids organized in alpha-helical structure which is required to inhibit IP3R. Residues <scene name='71/719863/Sceneip3inter/1'>K17, H20, Y21 and R26 | Bcl-2 localized at the ER membrane participates in the control of Ca2+ content and release. The inositol 1,4,5-trisphosphate receptor (IP3R) is the Ca2+ release channel localized in the ER. Its pro-apoptotic activity can be directly inhibited by Bcl-2, its homology domain 4 (BH4) being essential for this effect. <scene name='71/719863/Scenelucas/2'>BH4</scene> comprises 20 amino acids organized in alpha-helical structure which is required to inhibit IP3R. Residues <scene name='71/719863/Sceneip3inter/1'>K17, H20, Y21 and R26</scene> participate in the inhibition of IP3R because they are very accessible and proximal in the secondary structure. <ref> [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795776/ Alpha-Helical Destabilization of the Bcl-2-BH4-Domain Peptide Abolishes Its Ability to Inhibit the IP3 Receptor]</ref> | ||
=== Regulation of the mitochondrial pathway of apoptosis === | === Regulation of the mitochondrial pathway of apoptosis === | ||
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BH3-only proteins which belong to the Bcl-2 family activate pro-apoptotic proteins such as Bcl-2-associated X protein (Bax) or Bcl-2 antagonist/killer-1 (Bak) at the mitochondrion. When Bax or Bak are activated, they homo-oligomerize and form pores in the outer mitochondrial membrane which are necessary for the pro-apoptotic molecules (including second mitochondria-derived activator of caspase and cytochrome c) to escape. Then cytochrome c leads to the activation of caspases which are actually proteases that degrade the key proteins of the cell. | BH3-only proteins which belong to the Bcl-2 family activate pro-apoptotic proteins such as Bcl-2-associated X protein (Bax) or Bcl-2 antagonist/killer-1 (Bak) at the mitochondrion. When Bax or Bak are activated, they homo-oligomerize and form pores in the outer mitochondrial membrane which are necessary for the pro-apoptotic molecules (including second mitochondria-derived activator of caspase and cytochrome c) to escape. Then cytochrome c leads to the activation of caspases which are actually proteases that degrade the key proteins of the cell. | ||
On the other hand, Bcl-2 may prevent the activation and homo-oligomerization of Bax and Bak thus blocking the cell death. This is achieved by sequestering BH3-only proteins or activated | On the other hand, Bcl-2 may prevent the activation and homo-oligomerization of Bax and Bak thus blocking the cell death. This is achieved by sequestering BH3-only proteins or activated monomeric Bax and Bak. <scene name='71/719863/Scenebh1/2'>BH1</scene> and <scene name='71/719863/Scenebh2/2'>BH2</scene> are essential for <scene name='71/719863/Bcl2bax/1'>Bcl-2/Bax heterodimer</scene> formation. The conservation of each amino acid seems to be very important to this interaction. <ref>[http://www.nature.com.scd-rproxy.u-strasbg.fr/nature/journal/v369/n6478/pdf/369321a0.pdf BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax] </ref> <ref>[http://jcs.biologists.org/content/122/4/437 Control of mitochondrial apoptosis by the Bcl-2 family] </ref> | ||
Therefore, the neutralization of Bcl-2 is required for efficient cell-death. BH3 proteins Bad, Bim and Puma bind Bcl-2 and disable its anti-apoptotic activity. 4 hydrophobic residues of BH3 peptides occupy the hydrophobic pocket of Bcl-2 and the sequestered pro-apoptotic proteins are released. This hydrophobic pocket is formed by F97 and Y101 and conserved residues Asp in BH3 and Arg in the BH1 of Bcl-2 form a salt bridge which strenghtens the interaction. <ref>[http://www.cell.com/molecular-cell/fulltext/S1097-2765(05)01040-3 Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic Function]</ref> <ref> [http://www.cell.com/cancer-cell/fulltext/S1535-6108(02)00127-7 Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics] </ref> <ref>[http://www.nature.com/nrm/journal/v15/n1/full/nrm3722.html Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy] </ref> | Therefore, the neutralization of Bcl-2 is required for efficient cell-death. BH3 proteins Bad, Bim and Puma bind Bcl-2 and disable its anti-apoptotic activity. 4 hydrophobic residues of BH3 peptides occupy the hydrophobic pocket of Bcl-2 and the sequestered pro-apoptotic proteins are released. This hydrophobic pocket is formed by F97 and Y101 and conserved residues Asp in BH3 and Arg in the BH1 of Bcl-2 form a salt bridge which strenghtens the interaction. <ref>[http://www.cell.com/molecular-cell/fulltext/S1097-2765(05)01040-3 Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic Function]</ref> <ref> [http://www.cell.com/cancer-cell/fulltext/S1535-6108(02)00127-7 Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics] </ref> <ref>[http://www.nature.com/nrm/journal/v15/n1/full/nrm3722.html Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy] </ref> | ||
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NALP1 is a member of a NLR-family proteins. Its function is to activate the members of the proinflammatory caspase family which participate in the cytokine activation pathway (especially caspase-1). The Bcl-2 loop regions between the <scene name='71/719863/Scenebh3/3'>BH3</scene> and <scene name='71/719863/Scenelucas/2'>BH4</scene> bind NALP1. This interaction is exclusively reserved to two members of Bcl-2 family: Bcl-XL and Bcl-2 itself because this interacting region is poorly conserved in Bcl-2 family. By binding to NALP1, Bcl-2 inhibits the inflammatory caspase activation. Hence, it protects cells from the stress. | NALP1 is a member of a NLR-family proteins. Its function is to activate the members of the proinflammatory caspase family which participate in the cytokine activation pathway (especially caspase-1). The Bcl-2 loop regions between the <scene name='71/719863/Scenebh3/3'>BH3</scene> and <scene name='71/719863/Scenelucas/2'>BH4</scene> bind NALP1. This interaction is exclusively reserved to two members of Bcl-2 family: Bcl-XL and Bcl-2 itself because this interacting region is poorly conserved in Bcl-2 family. By binding to NALP1, Bcl-2 inhibits the inflammatory caspase activation. Hence, it protects cells from the stress. | ||
The posttranslational modifications found on the loops (rich in Ser and Thr residues) between <scene name='71/719863/Scenebh3/ | The posttranslational modifications found on the loops (rich in Ser and Thr residues) between <scene name='71/719863/Scenebh3/3'>BH3</scene> and <scene name='71/719863/Scenelucas/2'>BH4</scene> modify the anti-apoptotic activity of Bcl-2. Hence, the Bcl-2 binding to NALP1 can be affected by these modifications. <ref>[http://www.sciencedirect.com/science/article/pii/S0092867407003042 Bcl-2 and Bcl-XL Regulate Proinflammatory Caspase-1 Activation by Interaction with NALP1] </ref> | ||
=== Interaction with c-Myc === | === Interaction with c-Myc === | ||
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=== Cell cycle control === | === Cell cycle control === | ||
Bcl-2 is able to exert an anti-proliferative activity which is completely independant from its anti-apoptotic activity. In quiescent cells, Bcl-2 is responsible for faster G0/G1 arrest and for slower G0-G1/S transition. Posttranslational phosphorylations are very important for Bcl-2 anti-proliferative activity, for example, phosphorylation at Thr 56 by CDK1 delays G2/M exit. <scene name='71/719863/Scenelucas/2'>BH4</scene> and unstructured loop between <scene name='71/719863/Scenebh3/3'>BH3</scene> and <scene name='71/719863/Scenelucas/ | Bcl-2 is able to exert an anti-proliferative activity which is completely independant from its anti-apoptotic activity. In quiescent cells, Bcl-2 is responsible for faster G0/G1 arrest and for slower G0-G1/S transition. Posttranslational phosphorylations are very important for Bcl-2 anti-proliferative activity, for example, phosphorylation at Thr 56 by CDK1 delays G2/M exit. <scene name='71/719863/Scenelucas/2'>BH4</scene> and unstructured loop between <scene name='71/719863/Scenebh3/3'>BH3</scene> and <scene name='71/719863/Scenelucas/2'>BH4</scene> are crucial for this cell cycle control activity. <scene name='71/719863/Scenetr28/1'>Tyr28</scene> is critical for anti-proliferative activity, a point mutation reduces the ability of Bcl-2 to block the re-entry of quiescent cells. Inhibition of G0-G1/S is a consequence of increased levels of p130 and p27 which are regulated by Bcl-2. Bcl-2 also inhibits Raf-1 which normally activates ERK. ERK then inhibits Rb and this allows cell to pass the restriction point which leads to G1. Bcl-2 anti-proliferatif activity together with prevention of starvation-induced autophagy allow cells to survive in poor conditions. <ref> [http://www.sciencedirect.com/science/article/pii/S0167488903001824 Control of proliferation by Bcl-2 family members] </ref> | ||
== Diseases == | == Diseases == | ||
