The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
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:
In accordance to humans, conserved Glu/Gln and Trp residues are found in the IBM binding groove of drosophila Type III BIR domains. Drosophila Type III BIR domains bind N-terminal motifs that are revealed after removal of the initiator methionine. IBMs selective these BIR domains contain a conserved alanine residue in the first position followed by a variable position, a conserved proline or alanine in the third and another variable residue in the fourth position (^M?A.[AP].) (Eckelman,2008). The annotated instances for these domains are only conserved within Drosophila. However, BIR domain-containing proteins are also found in other Arthropoda, which may indicate further IBMs in families other than Drosophila.
Pattern: ^M{0,1}A.[AP].
Pattern Probability: 0.0000228
Present in taxon: Arthropoda
Interaction Domain:
BIR (PF00653) Inhibitor of Apoptosis domain (Stochiometry: 1 : 1)
PDB Structure: 1SE0
<a href="http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1SE0" title="" target="_blank"><img src="/media/pdb.ico.png"/>1SE0</a>
o See 4 Instances for LIG_BIR_III_3
o 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).
o 6 selected references:

o 9 GO-Terms:

o 4 Instances for LIG_BIR_III_3
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Protein NameGene NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q9VVP8_DROME skl 1 5 MAIPFFEEEHAPKSEPSGDQ TP 3 Drosophila melanogaster (Fruit fly)
RPR_DROME rpr 1 5 MAVAFYIPDQATLLREAEQK TP 1 Drosophila melanogaster (Fruit fly)
GRIM_DROME grim 1 5 MAIAYFIPDQAQLLARSYQQ TP 2 Drosophila melanogaster (Fruit fly)
HID_DROME W 1 5 MAVPFYLPEGGADDVASSSS TP 1 Drosophila melanogaster (Fruit fly)
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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