Sandbox Reserved 1122

This Sandbox is Reserved from 15/12/2015, through 15/06/2016 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1120 through Sandbox Reserved 1159.

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HUMAN BCL-2, ISOFORM1

spinqualitylabelsall models 3D STRUCTURE OF HUMAN BCL-2, ISOFORM1 (from residue 3 to 207) BASED ON NMR SPECTROSCOPY Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Human BCL-2, isoform 1 is an oncoprotein of 239 residues regulating cell death (apoptosis), notably acting as an anti-apoptotic. It is encoded by the BCL2 gene located on the 18th chromosome (63.12-63.32 Mb). There are 2 isoforms of this protein (𝛼 and 𝛽), produced by alternative splicing, and which differ by 2 aminoacids (residues 96 (A→T) and 110 (R→G))(ref). Alteration of this protein is a caused of many cancers, and is also likely to be involved in schyzophrenia and autoimmunity. You may include any references to papers as in: the use of JSmol in Proteopedia or to the article describing Jmol to the rescue. Structure Human BCL-2, isoform 1 is a 26kDa protein of 239 residues which is negatively charged at pH 7. The linear structure highlights 5 domains: BH4 (10-30), BH3 (93-107), BH1 (136-155), BH2 (187-202) and a transmembrane domain (218-239) (due to its poor behavior in solution, it has been replaced by a segment of Bcl-xl in the presented 3D structure). It organizes as eight alpha-helices: from 11 to 25 (1) , from 93 to 107 (2), from 109 to 118 (3), from 126 to 137 (4), from 144-163 (5), from 169 to 184 (6), from 186 to 191 (7) and from 194 to 202(8). There are also 3 turns (32-34, 123-125, 138-140). The 3rd alpha-helix is a 3(10) helix, whereas BCL-XL 3rd helix is a normal alpha-helix. Bcl-2 contains a hydrophobic groove on its surface that allows dimerization with other members of the Bcl-2 family. This region needs to be highly conserved to keep the ability of interacting with proapoptotic protein of the family, in fact, it has been shown that a mutation in this structure leads to the silencing of the dimerization thus may inhibit the activity of Bcl-2. The isoform 1 and 2 differs from two amino acid in the hydrophobic groove but this difference doesn’t induce any change in the conformation of this protein. However as expected, it affect the affinity with Bad and Bak proteins (from the Bcl-2 family). Indeed Bcl-2 isoform 1 shows to have a weaker affinity for Bad and Bak compared to isoform 2. Function IP3R inhibition Bcl-2 localized at the endoplasmic reticulum (ER) membranes participates in the control of Ca2+ content and release. The inositol 1,4,5-trisphosphate receptor (IP3R) is the primary Ca2+ release channel localized in the ER. Its pro-apoptotic activity can be directly inhibited by the Bcl-2, homology domain 4 (BH4) being essential and sufficient for this effect. BH4 comprises 20 amino acids (10-30) organized in alpha-helical structure which is required to inhibit IP3R. Residues K17, H20, Y21 and R26 participate in the inhibition of IP3R because they are very accessible and proximal in the secondary structure. Regulation of the mitochondrial pathway of apoptosis 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 the 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 and monomeric Bax and Bak. Therefore, the neutralization of Bcl-2 is required for eficient cell-death. BH3 proteins Bad, Bim and Puma bind Bcl-2 and disable its anti-apoptotic activity. BH3 peptides occupy the hydrophobic pocket of Bcl-2 and the sequestered pro-apoptotic proteins are released. Bcl-2 localized on external mitochondrial membrane can also inhibit the release of cytochrome c from mitochondria. Structural highlights This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.