Caspase-3 Regulatory Mechanisms: Difference between revisions

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Scott Eron, Banyuhay P. Serrano, Yunlong Zhao, Jaime Prilusky, Michal Harel, Alexander Berchansky

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 [[Image:Apop.png | thumb| Caspases in the apoptotic pathway]]
-Caspases are '''c'''ysteine-'''asp'''artic acid prote'''ases''' and are key protein facilitators for the faithful execution of apoptosis or programmed cell death. Dysregulation in the apoptotic pathway has been implicated in a variety of diseases such as neurodegeneration, cancer, heart disease and some metabolic disorders.  Because of the crucial role of caspases in the the apoptotic pathway, abnormalities  in their functions would cause a haywire in the apoptotic cascade and can be deleterious to the cell.  Caspases are thus being considered as therapeutic targets in apoptosis-related diseases.
+Caspases are '''''c'''''ysteine-'''''asp'''''artic acid prote'''''ases''''' and are key protein facilitators for the faithful execution of apoptosis or programmed cell death. Dysregulation in the apoptotic pathway has been implicated in a variety of diseases such as neurodegeneration, cancer, heart disease and some metabolic disorders.  Because of the crucial role of caspases in the the apoptotic pathway, abnormalities  in their functions would cause a haywire in the apoptotic cascade and can be deleterious to the cell.  Caspases are thus being considered as therapeutic targets in apoptosis-related diseases.
 Any apoptotic signal received by the cell causes the activation of initiator caspases (-8 and -9) by associating with other protein platforms to form a functional holoenzyme.  These initiator caspases then cleaves the executioner caspases -3, -6, -7.  Caspase-3 specifically functions to cleave both caspase-6 and -7, which in turn cleave their respective targets to induce cell death.  Aside from being able to activate caspase-6 and -7, caspase-3 also regulates caspase-9 activity, operating via a feedback loop.  These dual action of caspase-3 confers its distinct regulatory mechanisms, resulting a wider extent of its effects in the apoptotic cascade.
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 [[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 <scene name='Sandox_Bay_Serrano/Dimer_gray/1'>large and small subunit</scene> linked to each other by an intersubunit linker. Like other executioner caspases, caspase-3 has a short N-terminal prodomain.  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 interact via hydrophobic interactions 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 <scene name='Sandox_Bay_Serrano/Dimer_gray/1'>large and small subunit</scene> 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.
 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.