Caspase-3 Regulatory Mechanisms: Difference between revisions
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== Overview of Caspase-3 Structure == | == Overview of Caspase-3 Structure == | ||
<StructureSection load='2h5i_mm1-1.pdb' size='300' side='right' caption='Caspase-3 | <StructureSection load='2h5i_mm1-1.pdb' size='300' side='right' caption='Caspase-3 (PDB entry [[2h5i]])' scene='Sandox_Bay_Serrano/Monomer/1'> | ||
===Dimer Formation === | ===Dimer Formation === | ||
[[Image:Schematic.png | thumb | Procaspase-3 / Zymogen ]] | [[Image:Schematic.png | thumb | Procaspase-3 / Zymogen ]] | ||
Caspase-3 shares many structural characteristics with other caspases. It is synthesized in the cell in its zymogen form, consisting of an N-terminal prodomain followed by a large and small subunit linked to each other by an intersubunit linker. Like other executioner caspases, caspase-3 has a short N-terminal prodomain the function of which remains unknown. Maturation of the enzyme involves at least two cleavage- one to remove the N-terminal prodomain and the other to cleave the intersubunit linker. These two cleavage events have been shown to occur in a sequential fashion, with the cleavage between the small (p12) and large (p17) subunits preceding the pro domain removal. The high specificity of caspases directs the cleavage of the intersubunit linker at specific aspartate residue and generates the mature form of the enzyme. Caspase-3 in its functional form is a heterotetramer; each heterodimer is formed and stabilized by hydrophobic interactions between the large and small subunit. ß-sheets from each heterodimer then interact resulting in a 12-stranded <scene name='Sandox_Bay_Serrano/Scene01_dimer/2'>ß-sheet structure</scene>, around which α-helices are positioned. | Caspase-3 shares many structural characteristics with other caspases. It is synthesized in the cell in its zymogen form, consisting of an N-terminal prodomain followed by a large and small subunit linked to each other by an intersubunit linker. Like other executioner caspases, caspase-3 has a short N-terminal prodomain the function of which remains unknown. Maturation of the enzyme involves at least two cleavage- one to remove the N-terminal prodomain and the other to cleave the intersubunit linker. These two cleavage events have been shown to occur in a sequential fashion, with the cleavage between the small (p12) and large (p17) subunits preceding the pro domain removal. The high specificity of caspases directs the cleavage of the intersubunit linker at specific aspartate residue and generates the mature form of the enzyme. Caspase-3 in its functional form is a <scene name='Sandox_Bay_Serrano/Scene01_dimer/3'>heterotetramer</scene>; each heterodimer is formed and stabilized by hydrophobic interactions between the large and small subunit. ß-sheets from each heterodimer then interact resulting in a 12-stranded <scene name='Sandox_Bay_Serrano/Scene01_dimer/2'>ß-sheet structure</scene>, around which α-helices are positioned. | ||
The active pocket of caspase-3 is defined by <scene name='Sandox_Bay_Serrano/Monomer/2'>Cys-163 and His-121</scene>. Binding of a <scene name='Sandox_Bay_Serrano/Scene01_substrate/4'>substrate</scene>, such as DEVD-CHO to the active site of the enzyme induces a conformational change that allows the L2 and L2' loops to interlock and stabilize the active site <scene name='Sandox_Bay_Serrano/Scene01_substrate/3'></scene>. Like caspase-7, caspase-3 recognizes a Asp-X-X-Asp sequence as a cleavage site in its protein substrates. | The active pocket of caspase-3 is defined by <scene name='Sandox_Bay_Serrano/Monomer/2'>Cys-163 and His-121</scene>. Binding of a <scene name='Sandox_Bay_Serrano/Scene01_substrate/4'>substrate</scene>, such as DEVD-CHO to the active site of the enzyme induces a conformational change that allows the L2 and L2' loops to interlock and stabilize the active site <scene name='Sandox_Bay_Serrano/Scene01_substrate/3'></scene>. Like caspase-7, caspase-3 recognizes a Asp-X-X-Asp sequence as a cleavage site in its protein substrates. | ||
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=== Post translational Modification=== | === Post translational Modification=== | ||
Caspase-3 has been reported to be phosphorylated at Ser-150 by p38-MAPK. | Caspase-3 has been reported to be phosphorylated at Ser-150 by p38-MAPK and directly inhibits its activity. Conversely, phosphorylation of caspase-3 by protein kinase C zeta (PKC-ζ) was shown to promote autocleavage and activation. | ||
Aside from phosphorylation, caspase-3 is also known to be ubiquitinylated and nitrosylated, however the underlying mechanismsand effect of these modifications are still unclear. | |||
==== Natural Inhibitors==== | ==== Natural Inhibitors==== | ||