Caspase-3/Sandbox: Difference between revisions

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====Domains====

Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit (http://www.uniprot.org/uniprot/P42574)

====Folds and Motifs====

====Posttranslational Modifications====

Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa.

Acetylation: Protein which is posttranslationally modified by the attachment of at least one acetyl group; generally at the N-terminus.

Phosphoprotein: Protein which is posttranslationally modified by the attachment of either a single phosphate group, or of a complex molecule, such as 5'-phospho-DNA, through a phosphate group. Target amino acid is usually serine, threonine or tyrosine residues (mostly in eukaryotes), aspartic acid or histidine residues (mostly in prokaryotes).

S-nitrosylation: Protein which is posttranslationally modified by the attachment of a nitric oxide group on the sulfur atom of one or more cysteine residues.

Zymogen: The enzymatically inactive precursor of mostly proteolytic enzymes.

S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active site thiol. (http://www.uniprot.org/uniprot/P42574)

====Active Site/Ligand Binding====

====Active Site/Ligand Binding/Catalytic Activity====

This is a morph <scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/3'>1qx3 to 3kjf</scene> of caspase-3 from its uninhibited form to inhibition by novel irreversible inhibitor B92 ((3S)-3-({[(5S,10aS)-2-{(2S)-4-carboxy-2-[(phenylacetyl)amino]butyl}-1,3-dioxo-2,3,5,7,8,9,10,10a-octahydro-1H-[1,2,4]triazolo[1,2-a]cinnolin-5-yl]carbonyl}amino)-4-oxopentanoic acid). The <scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/9'>active site of caspase-3 binding to inhibitor B92</scene> involves<scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/12'>Gly121, Arg64, Gln161, Arg207, Ser205</scene>, and <scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/13'>catalytic residue, Cys163</scene>. (Wang, Watt et al. 2010)

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When cleaved into its active form, caspase-3 is then able to bind to its substrates via recognition of DEVD consensus sequence. Caspase-3, using its active site cysteine residue, is then able to cleave the substrate at the Asp residue occupying the P4 portion of the active site. This is a <scene name='Caspase-3/Sandbox/1qx3_2cjxv2_zdevdcmk/1'>morph</scene>([[1qx3]] to [[2cjx]])showing the binding of modified DEVD substrate (zDEVD-cmk) to the active site of caspase-3.

[[Image:1pau devd inhibition3.png|420px|right|thumb| Inhibitor DEVD-CHO bound to Caspase-3, [[1PAU]]]]

Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|- with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position. (http://www.uniprot.org/uniprot/P42574)

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===Function===

Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. (Nature. 1995 Jul 6;376(6535):37-43.

Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.

Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.)(http://www.uniprot.org/uniprot/P42574)

(Structural insights into its function)

Caspase-3/Sandbox: Difference between revisions

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@@ Line 9: / Line 9: @@
 ====Domains====
+Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit (http://www.uniprot.org/uniprot/P42574)
 ====Folds and Motifs====
 ====Posttranslational Modifications====
+Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa.
+Acetylation: Protein which is posttranslationally modified by the attachment of at least one acetyl group; generally at the N-terminus.
+Phosphoprotein: Protein which is posttranslationally modified by the attachment of either a single phosphate group, or of a complex molecule, such as 5'-phospho-DNA, through a phosphate group. Target amino acid is usually serine, threonine or tyrosine residues (mostly in eukaryotes), aspartic acid or histidine residues (mostly in prokaryotes).
+S-nitrosylation: Protein which is posttranslationally modified by the attachment of a nitric oxide group on the sulfur atom of one or more cysteine residues.
+Zymogen: The enzymatically inactive precursor of mostly proteolytic enzymes.
+S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active site thiol. (http://www.uniprot.org/uniprot/P42574)
-====Active Site/Ligand Binding====
+====Active Site/Ligand Binding/Catalytic Activity====
 <StructureSection applet load=1qx3.3kjf.morph.pdb' size='400' side='right' caption='Morph showing conformational changes between unbound and inhibitor bound ' scene='Caspase-3/Sandbox/Caspase_3_inhibition_morph/3'>
 This is a morph <scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/3'>1qx3 to 3kjf</scene> of caspase-3 from its uninhibited form  to inhibition  by novel irreversible inhibitor B92 ((3S)-3-({[(5S,10aS)-2-{(2S)-4-carboxy-2-[(phenylacetyl)amino]butyl}-1,3-dioxo-2,3,5,7,8,9,10,10a-octahydro-1H-[1,2,4]triazolo[1,2-a]cinnolin-5-yl]carbonyl}amino)-4-oxopentanoic acid).  The <scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/9'>active site of caspase-3 binding to inhibitor B92</scene> involves<scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/12'>Gly121, Arg64, Gln161, Arg207, Ser205</scene>, and <scene name='Caspase-3/Sandbox/Caspase_3_inhibition_morph/13'>catalytic residue, Cys163</scene>. (Wang, Watt et al. 2010)
@@ Line 19: / Line 28: @@
 When cleaved into its active form, caspase-3 is then able to bind to its substrates via recognition of DEVD consensus sequence. Caspase-3, using its active site cysteine residue, is then able to cleave the substrate at the Asp residue occupying the P4 portion of the active site. This is a <scene name='Caspase-3/Sandbox/1qx3_2cjxv2_zdevdcmk/1'>morph</scene>([[1qx3]] to [[2cjx]])showing the binding of modified DEVD substrate (zDEVD-cmk) to the active site of caspase-3.
 [[Image:1pau devd inhibition3.png|420px|right|thumb| Inhibitor DEVD-CHO bound to Caspase-3, [[1PAU]]]]
+Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|- with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position. (http://www.uniprot.org/uniprot/P42574)
@@ Line 25: / Line 38: @@
 ===Function===
+Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. (Nature. 1995 Jul 6;376(6535):37-43.
+Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
+Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.)(http://www.uniprot.org/uniprot/P42574)
 (Structural insights into its function)