ELM - Detail for LIG_BIR_III

Accession:	ELME000288
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 TAXON:7215 Type III BIR domains. TAXON:7215 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 TAXON:7215. However, BIR domain-containing proteins are also found in other Arthropoda, which may indicate further IBMs in families other than TAXON:7215.
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

IAP-binding motif (IBM)

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 TAXON:7215 Type III BIR domains. TAXON:7215 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 TAXON:7215. However, BIR domain-containing proteins are also found in other Arthropoda, which may indicate further IBMs in families other than TAXON:7215.

^M{0,1}A.[AP].

0.0000228

Arthropoda

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

PDB Structure: 1SE0

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).

Biological Process:
Apoptosis (also annotated in these classes: )
Anti-Apoptosis (also annotated in these classes: )
Protein Maturation By Peptide Bond Cleavage (also annotated in these classes: )
Regulation Of Apoptosis (also annotated in these classes: )
Cellular Compartment:
Cytosol (also annotated in these classes: )
Mitochondrion (also annotated in these classes: )
Molecular Function:
Protein Binding (also annotated in these classes: )
Protein Ubiquitination (also annotated in these classes: )

Acc., Gene-, Name	Start	End	Subsequence	Logic	#Ev.	Organism	Notes
Q9VVP8 skl Q9VVP8_DROME	1	5	MAIPFFEEEHAPKSEPSGDQ	TP	4	Drosophila melanogaster (Fruit fly)
Q24475 rpr RPR_DROME	1	5	MAVAFYIPDQATLLREAEQK	TP	1	Drosophila melanogaster (Fruit fly)	1SDZ 1SDZ
Q24570 grim GRIM_DROME	1	5	MAIAYFIPDQAQLLARSYQQ	TP	2	Drosophila melanogaster (Fruit fly)	1JD5 1SE0 1JD5 1SE0
Q24106 W HID_DROME	1	5	MAVPFYLPEGGADDVASSSS	TP	1	Drosophila melanogaster (Fruit fly)	1JD6 1JD6

Acc., Gene-, Name

Start

End

Subsequence

Logic

#Ev.

Organism

Notes

Q9VVP8 skl
Q9VVP8_DROME

MAIPFFEEEHAPKSEPSGDQ

Drosophila melanogaster (Fruit fly)

Q24475 rpr
RPR_DROME