Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Hu, Y. et al.

WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation.

The casp9 protein plays a critical role in apoptosis induced by a variety of death stimuli. A regulator of apoptosis, Apaf-1, binds to and activates pro-casp9 in the presence of cytochrome c and dATP, a requirement that is bypassed by deletion of the WD-40 repeats located in the C-terminal half of Apaf-1. In this report, we used constitutively active Apaf-1 mutant lacking the WD-40 repeat region to study the mechanism and regulation of pro-casp9 activation. Mutational analysis revealed that only a small portion of the CED-4 homologous region (residues 456-559) could be deleted without destroying the ability of Apaf-1-(1-559) to activate pro-casp9. Apaf-1 can self-associate to form oligomers. Disruption of Apaf-1 self-association by deletion (Delta109-559) or mutation of the P-loop region (K149R) abrogated Apaf-1- mediated pro-casp9 activation. Forced oligomerization of the caspase recruitment domain of Apaf-1 was sufficient for pro-casp9 activation. Dimerization of chimeric Fpk-pro-casp9 protein with the dimerizer drug FK1012 induced pro-casp9 processing and apoptosis in cells. Significantly, the C-terminal region containing WD-40 repeats interacted with its N-terminal CED-4 homologous region, as determined by immunoprecipitation experiments. Importantly, expression of the WD-40 repeat region inhibited Apaf-1 self-association and proteolytic activation of pro-casp9. These studies provide a mechanism by which Apaf-1 promotes autoactivation of pro-casp9 through Apaf-1 self-association, a process that is negatively regulated by the WD-40 repeats.[1]

References

WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. Hu, Y., Ding, L., Spencer, D.M., Núñez, G. J. Biol. Chem. (1998) [Pubmed]

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