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Publication Abstract from PubMed

Among all species, caspase-2 (C2) is the most evolutionarily conserved caspase required for effective initiation of apoptosis following death stimuli. C2 is activated through dimerization and autoproteolytic cleavage and inhibited through phosphorylation at Ser(139) and Ser(164) , within the linker between the caspase recruitment and p19 domains of the zymogen, followed by association with the adaptor protein 14-3-3, which maintains C2 in its immature form procaspase (proC2). However, the mechanism of 14-3-3-dependent inhibition of C2 activation remains unclear. Here, we report the structural characterization of the complex between proC2 and 14-3-3 by hydrogen/deuterium mass spectrometry (HDX-MS) and protein crystallography to determine the molecular basis for 14-3-3-mediated inhibition of C2 activation. Our data reveal that the 14-3-3 dimer interacts with proC2 not only through ligand-binding grooves but also through other regions outside the central channel, thus explaining the isoform-dependent specificity of 14-3-3 protein binding to proC2 and the substantially higher binding affinity of 14-3-3 protein to proC2 than to the doubly phosphorylated peptide. The formation of the complex between 14-3-3 protein and proC2 does not induce any large conformational change in proC2. Furthermore, 14-3-3 protein interacts with and masks both the nuclear localization sequence (NLS) and the C-terminal region of the p12 domain of proC2 through transient interactions in which both the p19 and p12 domains of proC2 are not firmly docked onto the surface of 14-3-3. This masked region of p12 domain is involved in caspase-2 dimerization. Therefore, 14-3-3 protein likely inhibits proC2 activation by blocking its dimerization surface.

14-3-3 protein binding blocks the dimerization interface of caspase-2.,Kalabova D, Filandr F, Alblova M, Petrvalska O, Horvath M, Man P, Obsil T, Obsilova V FEBS J. 2020 Jan 21. doi: 10.1111/febs.15215. PMID:31961068^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.