LIG_BIR_II_1
Accession: | |
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Functional site class: | IAP-binding motif (IBM) |
Functional site description: | The IBM specifically binds to the conserved BIR (baculoviral IAP repeat) domain that is found in Inhibitor of Apoptosis Proteins (IAPs). The motif is located at the N-terminal regions of caspases and pro-apoptotic IAP-antagonising proteins. In non-apoptotic cells, caspase activity is suppressed by the binding of IAPs to activated caspases. Upon apoptotic stimuli, pro-apoptotic IAP-antagonising proteins compete with the caspases for binding to the IAP or mediate their proteolytic degradation which leads to apoptosis promotion. |
ELMs with same func. site: | LIG_BIR_II_1 LIG_BIR_III_1 LIG_BIR_III_2 LIG_BIR_III_3 LIG_BIR_III_4 |
ELM Description: | Type II BIR domains contain conserved Glu and His residues in the IBM binding groove. They bind N-terminal motifs that are revealed either after removal of the initiator methionine or cleavage of the protein to produce a neo N-terminus. Similar to type III binding IBMs, type II-binding IBMs contain a conserved alanine residue in the first position. However, they tolerate serine as N-terminal residue. The last three positions of the motif are variable, which indicates a consensus motif of '^M?[AS]...' . All proteins known to have a function in apoptosis regulation contain alanine residues in the first position of their IBM, except for caspases 3 and 7. At the moment the role of these serine IBMs in the caspase IAP interactions is not fully understood (Eckelman,2008; Riedl,2001; Scott,2005). Peptide library scans indicate that type II BIR domains do select for an N-terminal serine residue of an IBM, but the selection is insignificant compared to alanine in P1 (Eckelman,2008). The regular expression for the motif contains three variable positions which render it rather unspecific. Four instances are found in mitochondrial proteins after removal of the mitochondrial targeting sequence or further proteolytic processing (Glutamate Dehydrogenase 1, P00367 (position 70-73); CLPX, O76031 (position 65-68), LRPPRC, P42704 (position 60-63) and 3-hydroxyisobutyrate dehydrogenase, P31937 (position 37-40)). The processing mechanisms of these proteins in the mitochondrion or other cellular compartments are unknown at the moment. Another instance is found in a cytosolic protein (NipSnap homolog 3A, Q9UFN0 (position 26-29)), which is processed by so far unidentified proteases. At the moment, a further specification of the regular expression by adding protease recognition sequences is not possible. Therefore no instances of type II binding IBMs can be included into ELM. |
Pattern: | ^M{0,1}[AS]... |
Pattern Probability: | 0.0003252 |
Present in taxon: | Metazoa |
Interaction Domain: |
BIR (PF00653)
Inhibitor of Apoptosis domain
(Stochiometry: 1 : 1)
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Abstract |
In multicellular organisms apoptosis has to be strictly regulated to maintain the equilibrium between cell proliferation and cell death. Dysregulation of apoptosis is linked to several diseases, especially cancer (Meier,2007). Inhibitor of Apoptosis Proteins (IAPs) are involved in apoptosis regulation but also exhibit several other functions in immunity, signal transduction via TNF-receptors, mitosis regulation etc. The first IAP was identified in the genome of Cydia pomonella granulosis virus, a baculovirus, where it blocks apoptotic mechanisms of the infected host cell to facilitate viral replication (Crook,1993). As a common structural element, IAPs possess one to three baculoviral IAP repeat domains (BIR domains, PF00653). These domains (built up by ~70 residues) are organised in 4 to 5 alpha-helices and a three-stranded zinc coordinated beta-sheet. To date there are eight known IAPs in humans: BIRC1 (NAIP), BIRC2 (c-IAP1), BIRC3 (c-IAP2), BIRC4 (XIAP), BIRC5 (survivin), BIRC6 (apollon), BIRC7 (ML-IAP), BIRC8 (ILP-2). BIRC 1-4 contain three BIR domains whereas in BIRC 5-8 only one BIR domain is found (Dubrez-Daloz,2008). According to conserved residues in their sequences the different kinds of BIR domains may be classified into type I, II and III domains. (Eckelman,2008). By direct suppression of initiator and effector caspases, apoptosis inhibition is mainly mediated by XIAP (BIRC4) (LaCasse,2008). Upon apoptotic stimuli, IAP-antagonising proteins such as SMAC (Second Mitochondria-derived Activator of Caspases) and HtrA2 liberate caspases from the inhibitory proteins by competitive binding, proteolytic degradation or ubiquitinylation and thereby promote apoptotic processes within the cell. As IAPs are often overexpressed in various human cancers and an elevated IAP expression is linked to poor prognosis, IAP inhibitors have been developed to target IAPs in cancer therapy. Peptides and small molecules based on the aminoterminal structure of SMAC have been shown to effectively promote apoptosis in human cancer cell lines as well as animal models (Zobel,2006; Vucic,2007). |
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An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif.
Crook NE, Clem RJ, Miller LK
J Virol 1993 Apr; 67 (4), 2168-74
PMID: 8445726
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Structural basis for the inhibition of caspase-3 by XIAP.
Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS
Cell 2001 Mar 9; 104 (5), 791-800
PMID: 11257232
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IAP proteins: blocking the road to death's door.
Salvesen GS, Duckett CS
Nat Rev Mol Cell Biol 2002 Jun; 3 (6), 401-10
PMID: 12042762
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XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily
conserved mechanism of IAPs.
Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS
EMBO J 2005 Feb 9; 24 (3), 645-55
PMID: 15650747
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Design, synthesis, and biological activity of a potent Smac mimetic that
sensitizes cancer cells to apoptosis by antagonizing IAPs.
Zobel K, Wang L, Varfolomeev E, Franklin MC, Elliott LO, Wallweber HJ, Okawa DC, Flygare JA, Vucic D, Fairbrother WJ, Deshayes K
ACS Chem Biol 2006 Sep 19; 1 (8), 525-33
PMID: 17168540
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The inhibitor of apoptosis proteins as therapeutic targets in cancer.
Vucic D, Fairbrother WJ
Clin Cancer Res 2007 Oct 15; 13 (20), 5995-6000
PMID: 17947460
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Lucifer's labyrinth--ten years of path finding in cell death.
Meier P, Vousden KH
Mol Cell 2007 Dec 14; 28 (5), 746-54
PMID: 18082600
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The mechanism of peptide-binding specificity of IAP BIR domains.
Eckelman BP, Drag M, Snipas SJ, Salvesen GS
Cell Death Differ 2008 May; 15 (5), 920-8
PMID: 18239672
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IAPs: more than just inhibitors of apoptosis proteins.
Dubrez-Daloz L, Dupoux A, Cartier J
Cell Cycle 2008 Apr 15; 7 (8), 1036-46
PMID: 18414036
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IAP-targeted therapies for cancer.
LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG
Oncogene 2008 Oct 20; 27 (48), 6252-75
PMID: 18931692
8 GO-Terms:
Please cite:
ELM-the Eukaryotic Linear Motif resource-2024 update.
(PMID:37962385)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement