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:
Type III BIR domains are characterised by conserved Glu/Gln and Trp residues in the IBM binding groove. They bind N-terminal motifs that are either revealed after proteolytic processing of the protein to produce a neo N-terminus or after removal of the initiator methionine. IBMs selective for these BIR domains contain a conserved alanine residue in the first position followed by a variable position, a conserved proline residue in the third and another variable residue in the fourth position (A.P.). In humans, the proline residue seems to be highly selective, as it enables a kink in the peptide chain, which is necessary for the accommodation of the P4 residue to its binding groove (Eckelman,2008). The motif`s regular expression (A.P.) is rather unspecific because of its brevity and its variable positions. Further specification is needed to use the regular expression within ELM. Specifying the regular expression by adding information about the N-terminal localisation of the motif (^M?A.P.) excludes neo N-terminal instances in proteolytically processed proteins. Two confirmed instances found in mitochondrial proteins are revealed after removal of the mitochondrial signal sequence. These examples (SMAC, Q9NR28 (position 56-59, 1G73) and HtrA2, O43464 (position 134-137)) cannot be entered into the database, as they do not match the regular expression for the motif. Attempts to specify the regular expression for neo N-terminal instances by adding residues commonly found in mitochondrial targeting sequences failed due to missing information about the mitochondrial processing of these proteins. Therefore the regular expression is only defined for proteins containing the motif at their unprocessed N-terminus (^M?A.P.).
Pattern: ^M{0,1}A.P.
Pattern Probability: 0.0000128
Present in taxon: Metazoa
Interaction Domain:
BIR (PF00653) Inhibitor of Apoptosis domain (Stochiometry: 1 : 1)
o See 1 Instance for LIG_BIR_III_1
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 10 selected references:

o 9 GO-Terms:

o 1 Instance for LIG_BIR_III_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Protein NameGene NameStartEndSubsequenceLogic#Ev.OrganismNotes
CHK1_HUMAN CHEK1 1 5 MAVPFVEDWDLVQTLGEGAY U 2 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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