User:Kévin Roger/Sandbox 953
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< User:Kévin Roger(Difference between revisions)
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=== Dimer Formation === | === Dimer Formation === | ||
| - | In each monomer of caspase-9, there are <scene name='67/676986/Beta-strands/1'>6 β-strands</scene> arranged in a '''β-sheet structure''' surrounding by α-helices<ref name=" EngCasp9" />. ß-sheets from each homodimer interaction resulting in a <scene name='67/676986/12_beta-strands/1'>large ß-sheet structure composed of 12 ß strains</scene>. Those β strands are located in the '''hydrophobic core''' of each monomer of caspase-9. The interaction between 2 monomers of caspase-9 is possible according to the interaction between 2 of the 6 β strand, called respectively <scene name='67/676986/Strand_6/1'>β6 and β6’</scene>. The β6 and β6’ | + | In each monomer of caspase-9, there are <scene name='67/676986/Beta-strands/1'>6 β-strands</scene> arranged in a '''β-sheet structure''' surrounding by α-helices<ref name=" EngCasp9" />. ß-sheets from each homodimer interaction resulting in a <scene name='67/676986/12_beta-strands/1'>large ß-sheet structure composed of 12 ß strains</scene>. Those β strands are located in the '''hydrophobic core''' of each monomer of caspase-9. The interaction between 2 monomers of caspase-9 is possible according to the interaction between 2 of the 6 β strand, called respectively <scene name='67/676986/Strand_6/1'>β6 and β6’</scene>. The β6 and β6’ strands are present with a '''variable constitution''' of amino acid in each caspase. In the engineering caspase-9, the β6 strand is composed by the <scene name='67/676986/Civsm/1'>CIVSM amino acids</scene> in position '''402 to 406'''<ref name=" EngCasp9" />. Those amino acids changes do not alter the conformation of the protein. For the wild-type caspase-9, the presence of Phe404 on strand β6 create a steric hindrance for the dimerization which is not the case with the engineering caspase-9. Therefore, it clearly seems that the variation of residues on this strand may likely contribute to the ability to form a dimer structure. The Phe404 is not present in the engineering dimer of caspase-9 so it does not contribute to the formation of the '''dimeric asymetric structure'''<ref name=" EngCasp9" />. |
=== Active site === | === Active site === | ||
| - | The active site is located on the '''surface''' of each monomer of caspase-9 because it needs an <scene name='67/676986/Hydrophilic_solvent/1'>hydrophilic environment</scene> (hydrophilic solvent) due to its function, '''hydrolysing''' the effector pro-caspase 3. There is therefore H20 molecules | + | The active site is located on the '''surface''' of each monomer of caspase-9 because it needs an <scene name='67/676986/Hydrophilic_solvent/1'>hydrophilic environment</scene> (hydrophilic solvent) due to its function, '''hydrolysing''' the effector pro-caspase 3. There is therefore H20 molecules in the actif site, however it is not represented in the crystal structure. Moreover, the actif site is composed of 4 loops, '''labelled L1 to L4'''<ref name=" EngCasp9" /> which form the active site of all monomer of caspase including caspase-9. The catalytic cysteine is located at the '''beginning of the L2 loops''' at the <scene name='67/676986/Catalytic_amino_acid/1'> position 287 remplaced in the crystal structure of dimeric caspase by a serine </scene> (Cys287->Ser287 because of a crystallization issue)<ref name=" EngCasp9" />. In the dimeric form, caspase-9 has a better catalytic activity because of the presence of two active sites (one in each monomer) in an '''opposite position''' (asymmetry of the dimer). The support of the L2' critical loop in the other monomer is crucial to have a catalytic activity<ref name=" EngCasp9" />. |
==Function of caspase-9== | ==Function of caspase-9== | ||
| - | Consequently to the caspase-9 activation, this initiator protein will associate with its substrate and activate it by cleavage. The substrate of caspase-9 is equivalent to an effector protein: it is the protein caspase-3. This protein is present downstream of caspase-9 in the mitochondrial cell death pathway and it is also present as a pro-enzyme before its activation. Once caspase-9 is activated | + | Consequently to the caspase-9 activation, this initiator protein will associate with its substrate and activate it by '''cleavage'''. The substrate of caspase-9 is equivalent to an effector protein: it is the '''protein caspase-3'''. This protein is present downstream of caspase-9 in the '''mitochondrial cell death pathway''' and it is also present as a pro-enzyme before its activation. Once caspase-9 is activated, it will cleave pro-caspase 3 in a specific sequence. This sequence is characterize by a '''high conserved motif''' : it corresponds to a sequence of '''Leu-Gly-His-Asp-|-Xaa''' where Xaa represents any amino acid. This sequence had absolutely an '''asparagine''' at '''position P1''' (caspase definition) and a preference for '''histidine''' at '''position P2''' <ref name="inhibitor">PMID: 23516580</ref>. The hydrolysis is carry out between the asparagine residue and the X residue. After all is said and done, the activated caspase 3 '''amplify the cell disassembly signal''', cleaving crucial cellular proteins leading to '''apoptosis'''. |
== References == | == References == | ||
<references/> | <references/> | ||
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