Caspase-3 Regulatory Mechanisms: Difference between revisions
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== Importance of Loop Orientation== | == Importance of Loop Orientation==<StructureSection load='2H5I' size='500' side='right' caption='Structure of Caspase-3 (PDB entry [[2H5I]])' scene=''> | ||
Caspases are extremely dependent on the orientation and geometry of their active site loops. If the loops are not ordered properly the enzyme fails to function. Caspase-3 has four active site loops on each half of the dimer constituting the active site bundle. Proteolytic activity is dependent on cleavage of an intersubunit linker, which releases loop 2 (L2) and L2’. <scene name='Caspase-3_Regulatory_Mechanisms/Scene2_nospin_labels/1'>L2'(green spheres) interacts with the opposite half of the dimer by holding up L2 (blue spheres) </scene>. This allows L2 to make critical contacts with L3 and L4, allowing them to organize the active site, bind substrate, and orient the nucleophilic cysteine 163 (bright green) so that it can cleave after aspartate residues. | Caspases are extremely dependent on the orientation and geometry of their active site loops. If the loops are not ordered properly the enzyme fails to function. Caspase-3 has four active site loops on each half of the dimer constituting the active site bundle. Proteolytic activity is dependent on cleavage of an intersubunit linker, which releases loop 2 (L2) and L2’. <scene name='Caspase-3_Regulatory_Mechanisms/Scene2_nospin_labels/1'>L2'(green spheres) interacts with the opposite half of the dimer by holding up L2 (blue spheres) </scene>. This allows L2 to make critical contacts with L3 and L4, allowing them to organize the active site, bind substrate, and orient the nucleophilic cysteine 163 (bright green) so that it can cleave after aspartate residues. | ||
Taking a closer look at L2 and L2’ we can see a critical interaction involving aspartate 169 on L2. This residue makes two hydrogen bonds with backbone amides of V189’ and E190’, stabilizing L2 in the proper position. This reinforcement allows L2 to contact L3 so as to twist the active site cysteine into the proper orientation to attack the substrate. In addition, L2 can now contact L4 at K260. This secures L4 and allows it to make contacts in the P4 position, which greatly influence substrate specificity. | Taking a closer look at L2 and L2’ we can see a critical interaction involving aspartate 169 on L2. This residue makes two hydrogen bonds with backbone amides of V189’ and E190’, stabilizing L2 in the proper position. This reinforcement allows L2 to contact L3 so as to twist the active site cysteine into the proper orientation to attack the substrate. In addition, L2 can now contact L4 at K260. This secures L4 and allows it to make contacts in the P4 position, which greatly influence substrate specificity. | ||
</StructureSection> | |||