ELM - Detail for LIG_BIR_III

Accession:	ELME000287
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 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,2008).
Pattern:	`DA.P.`
Pattern Probability:	`0.0003511`
Present in taxon:	Metazoa
Interaction Domain:	BIR (PF00653) Inhibitor of Apoptosis domain (Stochiometry: 1 : 1) PDB Structure: 1NW9

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:

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,2008).

DA.P.

0.0003511

Metazoa

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

PDB Structure: 1NW9

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
P55210 CASP7 CASP7_HUMAN	23	27	SANEDSVDAKPDRSSFVPSL	TP	1	Homo sapiens (Human)	3
Q7K4Z4 imd Q7K4Z4_DROME	30	34	VEGRLEKDAAPVDDNEPDNN	TP	1	Drosophila melanogaster (Fruit fly)
P55211 CASP9 CASP9_HUMAN	315	319	PGSNPEPDATPFQEGLRTFD	TP	4	Homo sapiens (Human)	1NW9 3D9T 1NW9 3D9T 2

Acc., Gene-, Name

Start

End

Subsequence

Logic

#Ev.

Organism

Notes

P55210 CASP7
CASP7_HUMAN

SANEDSVDAKPDRSSFVPSL

Homo sapiens (Human)

Q7K4Z4 imd
Q7K4Z4_DROME