Caspase-9

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.4RHW, 1JXQ, 1NW9, 2AR9, 3D9T, 3V3K, 3YGS84212371ENSG00000132906ENSMUSG00000028914P55211Q8C3Q9NM_001229NM_001278054NM_032996NM_001277932NM_015733NM_001355176NP_001220NP_001264983NP_127463NP_001264861NP_056548NP_001342105Similar to other caspases, caspase-9 has three domains: N-terminal pro-domain, large subunit, and a small subunit. The N-terminal pro-domain is also called the long pro-domain and this contains the caspase activation domain (CARD) motif. The pro-domain is linked to the catalytic domain by a linker loop.Within the cell, caspase-9 in humans is found in the mitochondria, cytosol, and nucleus.Active caspase-9 works as an initiating caspase by cleaving, thus activating downstream executioner caspases, initiating apoptosis. Once activated, caspase-9 goes on to cleave caspase-3, -6, and -7, initiating the caspase cascade as they cleave several other cellular targets.Negative regulation of caspase-9 occurs through phosphorylation. This is done by a serine-threonine kinase, Akt, on serine-196 which inhibits the activation and protease activity of caspase-9, suppressing caspase-9 and further activation of apoptosis. Akt acts as an allosteric inhibitor of caspase-9 because the site of phosphorylation of serine-196 is far from the catalytic site. The inhibitor affects the dimerization of caspase-9 and causes a conformational change that affects the substrate-binding cleft of caspase-9.A deficiency in caspase-9 largely affects the brain and its development. The effects of having a mutation or deficiency in this caspase compared to others is detrimental. The initiating role caspase-9 plays in apoptosis is the cause for the severe effects seen in those with an atypical caspase-9.The effects of abnormal caspase-9 levels or function impacts the clinical world. The impact caspase-9 has on the brain can lead to future work in inhibition through targeted therapy, specifically with diseases associated with the brain as this enzyme may have take part in the developmental pathways of neuronal disorders.Through alternative splicing, four difference caspase-9 variants are produced.Caspase-9 has been shown to interact with: