Abstract
Direct IAP binding protein with low pI/second mitochondrial activator of caspases, HtrA2/Omi and GstPT/eRF3 are mammalian proteins that bind via N-terminal inhibitor of apoptosis protein (IAP) binding motifs (IBMs) to the baculoviral IAP repeat (BIR) domains of IAPs. These interactions can prevent IAPs from inhibiting caspases, or displace active caspases, thereby promoting cell death. We have identified several additional potential IAP antagonists, including glutamate dehydrogenase (GdH), Nipsnap 3 and 4, CLPX, leucine-rich pentatricopeptide repeat motif-containing protein and 3-hydroxyisobutyrate dehydrogenase. All are mitochondrial proteins from which N-terminal import sequences are removed generating N-terminal IBMs. Whereas most of these proteins have alanine at the N-terminal position, as observed for previously described antagonists, GdH has an N-terminal serine residue that is essential for X-linked IAP (XIAP) interaction. These newly described IAP binding proteins interact with XIAP mainly via BIR2, with binding eliminated or significantly reduced by a single point mutation (D214S) within this domain. Through this interaction, many are able to antagonise XIAP inhibition of caspase 3 in vitro.
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Accession codes
Abbreviations
- IAP:
-
inhibitor of apoptosis
- BIR:
-
baculoviral IAP repeat
- Diablo:
-
direct IAP binding protein with low pI
- Smac:
-
second mitochondrial activator of caspases
- GdH:
-
glutamate dehydrogenase
- LRPPR:
-
leucine-rich pentatricopeptide repeat motif-containing protein
- 3HB:
-
3 hydroxyisobutyrate dehydrogenase
- Nsp:
-
Nipsnap
- IBM:
-
IAP binding motif
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Acknowledgements
We acknowledge Lisa Connolly, Andrew Clippingdale and Robert Moritz from the Joint Protein Service Facility for their mass spectrometric analysis, Diep Chu for recombinant Diablo protein and David Huang for vectors provided. AMV is a recipient of an Australian Research Council (ARC) QEII fellowship. DLV is an National Health and Medical Research (NHMRC) Senior Principle Research Fellow. PGE, JS and CJH are all supported by NHMRC Career Development fellowships. This work was supported by NHMRC Program Grant (257502) and a Leukemia and Lymphoma Society Center Grant. CH's work is supported by grants from the ARC (#DP0343431) and NHMRC (#284513).
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Verhagen, A., Kratina, T., Hawkins, C. et al. Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ 14, 348–357 (2007). https://doi.org/10.1038/sj.cdd.4402001
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DOI: https://doi.org/10.1038/sj.cdd.4402001
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