Sandbox Reserved 1122: Difference between revisions
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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> | ||
