Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs.
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.
Verhagen
A M
AM
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Kratina
T K
TK
Hawkins
C J
CJ
Silke
J
J
Ekert
P G
PG
Vaux
D L
DL
D000409:Alanine; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism*; D000090263:Leucine-Rich Repeat Proteins; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D040901:Proteomics; D012694:Serine; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C499605:Diablo protein, mouse; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D000090263:Leucine-Rich Repeat Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D012694:Serine; D005969:Glutamate Dehydrogenase; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D000409:Alanine