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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.

Original publication

DOI

10.1038/sj.cdd.4402001

Type

Journal article

Publication Date

02/2007

Volume

14

Pages

348 - 357

Keywords

Alanine, Amino Acid Motifs, Amino Acid Sequence, Animals, Carrier Proteins, Caspase Inhibitors, Enzyme Inhibitors, Glutamate Dehydrogenase, High-Temperature Requirement A Serine Peptidase 2, Humans, Inhibitor of Apoptosis Proteins, Mammals, Mice, Mitochondrial Proteins, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Proteins, Proteomics, Serine, Serine Endopeptidases, X-Linked Inhibitor of Apoptosis Protein