caspase-3; CPP32/YAMA; PARP cleavage protease; apopain (CASP3, CPP32)

Function

• role 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 sterol regulatory element binding proteins (SREBPs) & activates them; cleaves between the basic helix-loop-helix leucine zipper domain & the membrane attachment domain
• cleaves & activates caspase-6, caspase-7 & caspase-9
• involved in the cleavage of huntingtin
• cleavage by granzyme B, caspase-6, caspase-8 & caspase-10 generates the two active subunits
• additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease
• S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines & denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity
• Fas thus 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
• strict requirement for an Asp residue at positions P1 & P4
• preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|- with a hydrophobic amino-acid residue at P2 & a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position

Inhibition:

• inhibited by isatin sulfonamides

Structure

• heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kD (p17) & a 12 kD (p12) subunit
• active heterodimers between the small subunit of caspase-7 protease & the large subunit of caspase-3 also occur & vice versa
• belongs to the peptidase C14 family

Compartment

cytoplasm

Expression

• expressed in lung, spleen, heart, liver & kidney > brain & skeletal muscle, & low in testis
• also found in many cell lines
• highest expression in cells of the immune system

More general terms

• caspase
• phosphoprotein

Additional terms

• apoptotic protease-activating factor 1; APAF-1 (APAF1, KIAA0413)
• caspase 3 substrates

Database

• UniProt: http://www.uniprot.org/uniprot/P42574.html
• OMIM: https://mirror.omim.org/entry/600636
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=836
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:836