The Eukaryote Linear Motif resource for Functional Sites in Proteins
LIG_BIR_III_2 287
 
 << LIG_BIR_III_1 <<  Menu  >> LIG_BIR_III_3 >> 
 
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: LIG_BIR_II_1 LIG_BIR_III_1 LIG_BIR_III_2 LIG_BIR_III_3 LIG_BIR_III_4
Description: Type III BIR domains are characterised by conserved Glu/Gln and Trp residues in the IBM binding groove. They bind neo N-terminal motifs that are revealed after cleavage of pro-caspases into effector or initiator caspases. As caspases are commonly cleaved by other caspases or granzyme B, the motif is predominantly found C-terminal of aspartate residues. IBMs selective for type III BIR domains contain a conserved alanine residue in the first position followed by a variable position, a conserved proline in the third and another variable residue in the fourth position (DA.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 into its binding groove (Eckelman et al. 2008).
Pattern: DA.P. (Probability: 0.0003511)
Present in taxons: Metazoa
PDB Structure: 3D9T
<img src="/media/pdb.ico.png"/><a href="http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3D9T" target="_blank">3D9T</a>
Interaction Domain:

BIR (PF00653)
Inhibitor of Apoptosis domain
(Stochiometry: 1 : 1)

o See 3 Instances for LIG_BIR_III_2


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 et al. 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 et al. 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 et al. 2008).
By direct suppression of initiator and effector caspases apoptosis inhibition is mainly mediated by XIAP (BIRC4) (LaCasse et al. 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 (Sobel, 2006; Vucic, 2007).

o 9 selected references:

o 9 GO-Terms:

o 3 Instances for LIG_BIR_III_2
(click table headers for sorting)
SequenceStartEndSubsequence
Instance LogicPDB Organism
Q7K4Z4_DROME 30 34 VEGRLEKDAAPVDDNEPDNN true positive --- Drosophila melanogaster (Fruit fly)
CASP7_HUMAN 23 27 SANEDSVDAKPDRSSFVPSL true positive --- Homo sapiens (Human)
CASP9_HUMAN 315 319 PGSNPEPDATPFQEGLRTFD true positive 1NW9
3D9T
 Homo sapiens (Human)

Please cite: ELM - the database of eukaryotic linear motifs (PMID:22110040)

ELM data can be downloaded and distributed for non-commercial use according to the ELM Software License Agreement

feedback@elm.eu.org