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).