Caspase-3/Sandbox: Difference between revisions

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====Folds and Motifs====
====Folds and Motifs====
====Posttranslational Modifications====
====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.
Caspase-3 is translated as a zymogen. Activation occurs via cleavage by initiator caspases, such as caspase-8, -9, and -10, and by granzyme B to generate the p12(small) and p17(large) subunits.
Acetylation: Protein which is posttranslationally modified by the attachment of at least one acetyl group; generally at the N-terminus. Residue 1 modified by N-acetylmethionine (ref 12)
(http://www.uniprot.org/uniprot/P42574)


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). Residue 26 perhaps modified by Phosphoserine.
=====S-Nitrosylation=====
An ambient level of nitric oxide has antiapoptotic effects via S-nitrosylation of caspase-3 zymogens at its catalytic Cys163 residue perhaps because it directly associates with all 3 NOS isoforms. S-nitrosylation effectively inhibits the enzyme activity of caspase-3 (Mannick, 2007). NO and S-nitrosoglutathione (GSNO) reacts nonspecifically to all cysteine residues of caspase-3 (Mitchell, 2005). Caspase-3 nitrosylation at a second cysteine residue (Cys47, Cys220, or Cys 264) may have further antiapoptotic effects by leading to its association with acid sphingomyelinase (ASM). ASM inhibits cleavage and activation of caspase-3 by initiator caspases, such as caspase-8 and caspase-9 (Mannick, 2007).  


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. Residue 163 modified by S-nitrosocysteine in inhibited form.
Thioredoxin, the main intracellular oxidoreductase, does not inhibit caspase-3 activity. However, Trx-Cys73-SNO inhibits apoptosis by decreasing caspase-3 activity via transnitrosylation at Cys163 catalytic residue. This reaction is reversible, although this is not as likely since Cys163 on caspase-3 is more nucleophilic than Cys73 on Trx. GSNO is capable of transferring its nitroso-group to Trx-Cys73, which in turn can S-nitrosylate caspase-3, leading to inactive caspase-3 (Mitchell, 2005).


Zymogen: The enzymatically inactive precursor of mostly proteolytic enzymes.
In human B- and T-cell lines, nitrosylation of caspase-3 depends on localization: mitochondrial but not cytoplasmic caspase-3 zymogens are S-nitrosylated. S-nitrosylation may prevent improper autoactivation in the mitochondria due to close proximity in the intermembrane space (Mannick, 2001).  Mitochondrial caspase-3 is released into the cytoplasm and becomes denitrosylated when FasL binds Fas receptor (Mannick, 2001). Fas receptor activation by FasL activates the extrinsic pathway of apoptosis through activation of caspase-8, which can either directly cleave procaspase-3 to caspase-3 or lead to Bid cleavage to tBid. tBID then permeates into the mitochondria, leading to cytochrome c release, apoptosome formation with caspase-9, and finally caspase-3 cleavage to its activated form. Smac/DIABLO is also released from the mitochondria and leads to inhibition of XIAP (X-linked inhibitor of apoptosis), abrogating its inhibitory effect on caspase-3 activity within the cytosol. XIAP also functions as an E3 ubiquitin ligase, targeting caspase-3 for proteasomal degradation (Nakamura, 2010). Aside from this, Fas-induced apoptosis also leads to denitrosylation of caspase-3 and therefore activation by freeing its catalytic Cys residue (Mannick, 1999).  Perhaps, this denitrosylation occurs via transnitrosylation of XIAP RING domain at Cys450, which in effect inhibits its E3 ligase activity. This further prolongs caspase-3 activity by blocking its degradation, and thus promotes increased cell death (Nakamura, 2010). Thus, S-nitrosylation of caspases inhibits caspase activation and apoptosis, whereas denitrosylation activates caspases and promotes apoptosis (Mannick, 2007).  


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)
=====Other=====
The first residue of caspase-3, Met1, is posttranslationally modified as N-acetylmethionine. Ser26 is possibly modified as Phosphoserine.(http://www.uniprot.org/uniprot/P42574)




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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)
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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(Fuentes-Prior and Salvesen, 2004)
(Fuentes-Prior and Salvesen, 2004)


SNO-caspases have been suggested to promote cell injury and death in neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases, by transnitrosylating XIAP (Nakamura, 2010).


==Evolutionarily Related Proteins==
==Evolutionarily Related Proteins==
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