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Five members of the human family of inhibitor of apoptosis proteins including NAIP have been shown to be antiapoptotic in various systems. To date, a mechanism for the antiapoptotic effect of NAIP has not been elucidated. To investigate NAIP function, we found cytoprotection of NAIP-expressing primary cortical neurons treated to undergo caspase-3-dependent apoptosis. The additional treatment of these neurons with the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone did not result in increased survival. Similar cytoprotective effects were obtained using HeLa cells transiently transfected with a NAIP N-terminal construct and treated to undergo a caspase-3-dependent cell death. To examine whether NAIP inhibits caspases directly, recombinant N-terminal NAIP protein containing BIR domains was overexpressed, purified, and tested for caspase inhibition potential. Our results demonstrate that inhibition of caspases is selective and restricted to the effector group of caspases, with<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>values as low as \u223c14 n<jats:sc>m<\/jats:sc>for caspase-3 and \u223c45 n<jats:sc>m<\/jats:sc>for caspase-7. Additional investigations with NAIP fragments containing either one or two NAIP BIRs revealed that the second BIR and to a lesser extent the third BIR alone are sufficient to mediate full caspase inhibition.<\/jats:p>","DOI":"10.1523\/jneurosci.22-06-02035.2002","type":"journal-article","created":{"date-parts":[[2018,4,13]],"date-time":"2018-04-13T22:30:10Z","timestamp":1523658610000},"page":"2035-2043","source":"Crossref","is-referenced-by-count":145,"title":["The Neuronal Apoptosis Inhibitory Protein Is a Direct Inhibitor of Caspases 3 and 7"],"prefix":"10.1523","volume":"22","author":[{"given":"Johannes K. 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