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Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs

Anne M Verhagen*, Elizabeth J Coulson and David L Vaux

Author Affiliations

The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia

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Genome Biology 2001, 2:reviews3009-reviews3009.10  doi:10.1186/gb-2001-2-7-reviews3009

The electronic version of this article is the complete one and can be found online at:

Published:5 July 2001

© 2001 BioMed Central Ltd


Apoptosis is a physiological cell death process important for development, homeostasis and the immune defence of multicellular animals. The key effectors of apoptosis are caspases, cysteine proteases that cleave after aspartate residues. The inhibitor of apoptosis (IAP) family of proteins prevent cell death by binding to and inhibiting active caspases and are negatively regulated by IAP-binding proteins, such as the mammalian protein DIABLO/Smac. IAPs are characterized by the presence of one to three domains known as baculoviral IAP repeat (BIR) domains and many also have a RING-finger domain at their carboxyl terminus. More recently, a second group of BIR-domain-containing proteins (BIRPs) have been identified that includes the mammalian proteins Bruce and Survivin as well as BIR-containing proteins in yeasts and Caenorhabditis elegans. These Survivin-like BIRPs regulate cytokinesis and mitotic spindle formation. In this review, we describe the IAPs and other BIRPs, their evolutionary relationships and their subcellular and tissue localizations.

Gene organization and evolutionary history

The inhibitor of apoptosis proteins (lAPs) were originally identified in baculoviruses, where they provide a mechanism for enhancing viral propagation through inhibition of defensive apoptosis by host insect cells [1,2]. Cellular IAPs were subsequently described in insects and vertebrates [3,4,5,6,7,8,9]. In recent times, it has become apparent that there is a second group of BIR-domain-containing proteins (BIRPs) carried by organisms such as Caenorhabditis elegans and yeasts as well as mammals and insects that can be distinguished from IAPs both by function and by structural features of their BIR domains (reviewed by Miller [10]). The domain structures of various BIRPs is shown in Figure 1a, and the relationship of different BIR domains to each other is illustrated by the phylogenetic tree in Figure 1b and an alignment of a selection of BIR domains is given in Figure 1c. Table 1 lists the chromosomal localizations of the genes encoding human BIRPs as well as their tissue expression patterns and the disease situations in which alterations of the genes have been observed.

thumbnailFigure 1. Structure and evolution of BIRPs. (a) Domain structures of BIRPs in mammals (humans), insects, nematodes and yeast. The length of each protein (in amino acids) is shown on the right. IAPs have type 1 BIR domains (dark blue), whereas type 2 BIR domains (light blue) are found in Survivin-like BIRPs. (b) The evolutionary relationship of BIR domains. A phylogenetic tree was generated using the parsimony option of the PHYLIP Phylogeny Inference Package (version 3.5c) [72], from BIR domains aligned by the Clustal W1.7 program. The accession numbers and regions used in the analysis are shown in Table 2. Default settings were used; the order of the sequences was jumbled 10 times and the degree of certainty for each node (the bootstrap value, shown on the Figure) was calculated from 100 random replicates. All bootstrap values greater than 50 and selected others are shown. The values for placement of ML-IAP with NAIP BIR3 and BIR2 domains are very low, and trees calculated using distance methods placed ML-IAP BIR with the BIR3 domains of XIAP, cIAP-1 and cIAP-2. Also, note that the alignment used to generate this tree does not include the carboxy-terminal α-helical extension that is conserved between the BIR3 domains of XIAP, cIAP-1, cIAP-2 and ML-IAP but not NAIP. (c) Two types of BIR domain. An alignment of a selection of BIR domains illustrates the difference between BIR domains present within classical IAPs (top four sequences) and within other BIRPs (bottom four). Aligned regions are as given in Table 2. Amino acids that are conserved in all BIR domains are highlighted. Type 1 BIR domains are approximately 70 amino acids long, whereas type 2 BIR domains are longer.

Table 1. Properties of human BIRPs

Table 2. Accession numbers of BIRPs shown in Figure 1b and regions used in the phylogenetic analysis

The first group of BIRPs encompasses those that inhibit cell death; they are appropriately called IAPs. These proteins have between one and three BIR domains and also often have a RING-finger domain. IAPs have been identified in several multicellular organisms from Drosophila to mammals, but are not present in plants, yeasts, protozoans or C. elegans. The close relationship between baculoviral IAPs and insect IAPs suggests that baculoviral IAPs may have been acquired through gene transfer from host insect cells [11]. The BIR domains of IAPs can be grouped into several subtypes (Figure 1b). The three BIR domains - BIR1, BIR2 and BIR3 - of human XIAP, cIAP-1 and cIAP-2 fall into three different subgroups, suggesting gene duplication of an ancestral IAP gene encoding three BIR domains and a RING finger.

The gene encoding murine XIAP/MIHA/hILP/BIRC4 spans approximately 20 kilobases (kb) and the protein is encoded by six exons [12]. The initiation codon, the BIR1 and BIR2 domains and half of the BIR3 domain is encoded by exon 1. The rest of the BIR3 domain is encoded by exons 2 and 3; exons 4 and 5 encode the following non-structural region and exon 6 encodes the carboxy-terminal RING-finger domain and stop codon. The structures of the genes for cIAP-1/MIHB/hiap2/BIRC2 and cIAP-2/MIHC/hiap1/BIRC3 are reportedly similar to that of XIAP (referred to as unpublished data by Farahani et al. [12]). Mammalian cIAP-1 and cIAP-2 are very similar to each other and their genes are tightly linked (about 12 kb apart), suggesting a relatively recent gene-duplication event [13]. Both proteins have three BIR domains, a caspase recruitment domain (CARD) and a RING finger. The recently identified IAP ML-IAP/LIVIN/KIAP/BIRC7 has only one BIR domain which is most highly related to the BIR3 domains of cIAP-1, cIAP-2 and XIAP, particularly in having an α-helical extension carboxy-terminal to the BIR domain [14,15,16].

There are thought to be six tightly linked NAIP genes in mice and humans [17,18,19]. The BIR domains of NAIPs are more distantly related to the BIR domains of the other mammalian IAPs (see Figure 1b) and NAIPs do not have a RING-finger domain but do have a nucleotide-binding domain at their carboxyl terminus [5,20]. There are two Drosophila IAPs, DIAP1 and DIAP2, which have two or three BIR domains, respectively and which each have a carboxy-terminal RING-finger domain [4]. Another insect IAP, SflAP from Spodoptera frugiperda, has also recently been described, with two BIR domains and a carboxy-terminal RING-finger domain [11]. There are several baculoviral IAPs; most have two BIR domains and a carboxy-terminal RING-finger domain [1,2].

The second group of BIRPs includes mammalian Survivin/BIRC5 and Bruce/BIRC6, C. elegans BIR-1 and BIR-2 (shown as CeBIR-1 and CeBIR-2 in Figure 1), yeast Spbir1P and ScBIR1P and Drosophila proteins d-Bruce and Deterin [21,22,23,24,25]. Apart from their BIR domains, these proteins are otherwise highly variable in size and structure. They have slightly larger BIR domains than those of the IAPs (see Figure 1c) and there is a conserved intron after the invariant glycine-encoding codon in the BIR-domain-encoding region that is not present in IAP genes. The presence of the Survivin-like BIRPs in a wide range of organisms and their conserved function suggests that they represent the earliest BIRPs. It is possible that, following a gene-duplication event, the BIR domains in IAPs evolved to have a different function, namely to interact with and inhibit caspases. The genes for both murine and human Survivin have been described, and both comprise four exons, with exons 2 and 3 encoding the BIR domain [26,27,28].

Characteristic structural features

BIR domains are characterized by a number of invariant amino acids, including three conserved cysteines and one conserved histidine residue within the sequence CX2CX16HX6-8C (Figure 1c). Within IAPs, BIR domains are typically about 70 amino acids long, but they can be more than 100 amino acids long in other BIRPs. The structures of the cIAP-1 BIR3 domain and the XIAP BIR2 and BIR3 domains are very similar, indicating that BIR domains typically comprise a series of four or five α helices and a three-stranded β sheet with a single zinc ion coordinated by the conserved cysteine and histidine residues [29,30,31,32,33].

RING fingers, a type of zinc finger, are present in diverse proteins. A carboxy-terminal RING finger domain is present in most of the IAPs and has, for XIAP and c-IAP-1, been shown to have ubiquitin protein ligase activity, directly regulating self-ubiquitination and degradation [34]. RING domains are characterized by the presence of a set of invariant metal-binding residues (C3HC4) that coordinate two zinc ions [35]. The equine herpes virus protein RING has been shown to consist of an amphipathic α helix next to a triple-stranded β sheet [36].

The c-IAP1 and c-IAP2 proteins have caspase recruitment domains (CARDs) between their three BIR domains and the RING-finger domain. The name relates to the ability of CARDs within adaptor proteins such as Apaf-1 to interact with CARDs within some initiator caspases (see later), such as caspase 9 [37]. The CARD fold is related to other protein-protein interaction domains found in proteins involved in cell death and elsewhere, such as the death domain, the death effector domain and the pyrin domain. The only IAPs described to date that possess a CARD are cIAP-1 and cIAP-2, and the function of this domain in these proteins is not known. Protein-protein interactions of cIAP-1 or cIAP-2 CARDs with CARDs of other proteins have not been described, nor have the CARDs been shown to self-associate. The structure of cIAP-1 and cIAP-2 CARDs have not yet been described, although CARDs from other proteins have been shown to comprise six or seven tightly packed anti-parallel α helices, with both charged regions and hydrophobic regions mediating CARD-CARD interactions [38,39,40,41,42].

Localization and function

BIRPs involved in inhibiting cell death: IAPs

The tissue and subcellular localization of mammalian IAPs varies (see Table 1) and may be important in determining the relative contribution of different IAPs to cell-death regulation in different cell types and in response to different apoptotic stimuli.

XIAP appears to be widely expressed [5,6]. It has a cytoplasmic location and has been reported to inhibit cell death in response to a variety of apoptotic stimuli including ultraviolet irradiation, tumor necrosis factor (TNF), Fas ligand, and a number of toxic drugs (reviewed by LaCasse et al. [43]). XIAP very efficiently interacts with and inhibits active caspases 3, 7 and 9 [44,45,46]. Interaction of XIAP via its RING-finger domain with bone morphogenetic protein (BMP) type I receptors has also been reported, which would presumably enable some XIAP to localize to the plasma membrane [47]. A role for XIAP in regulating the BMP receptor signaling pathway by linking the receptor to downstream signaling molecule TAB1 has been proposed.

The cIAP-1 and cIAP-2 proteins were initially identified in a complex with TNF receptor 2, an indirect association resulting from direct interaction with TNF-receptor-associated factors (TRAFs) 1 and 2 involving the BIR and TRAF domains of the respective proteins [3]. The expression of cIAP-1 and cIAP-2 is increased following activation of the NF-κB transcription factor by the TNF receptor, and these IAPs may have a role in protecting cells from TNF-induced apoptosis by reducing the amount of caspase 8 activation [48]. Exactly how they do this is unclear, because caspase 8 can not be directly inhibited by cIAP-1 or -2 or by any other known IAPs [49]. Perhaps they act by inhibiting downstream caspases such as caspase 3, preventing the feedback loop involved in the further activation of upstream caspase 8. The cIAP-1 and cIAP-2 proteins have been shown directly to inhibit the activity of caspases 3 and 7 [49]. Although cIAP-1 and cIAP-2 can be found within the TNF-R complex, and they are presumably localized in part to the cell membrane, it is not clear what proportion of total cellular cIAP-1 or cIAP-2 this represents, and when transiently transfected into cells, cIAP-1 has a perinuclear localization [50].

The recently described mammalian IAP ML-IAP is detectable in embryonic tissue, selected adult tissues and several cancer cell lines, particularly in melanoma cell lines (see Table 1) [14,15,16]. One study reported expression predominantly in the nucleus but also in filamentous structures in the cytoplasm, whereas only cytoplasmic expression was reported in another study. Although ML-IAP has only one BIR domain, it is reported to interact with and inhibit both the initiator caspase 9 and effector caspases 3 and 7; it inhibits cell death induced through death receptors, by overexpression of the cell-death pathway proteins FADD, Bax, RIP, RIP3 and DR3 or in response to various toxic drugs.

The first NAIP gene was identified as a candidate gene defective in spinal muscular atrophy [5,20]. It is now clear that deletion of a neighboring gene encoding the protein survival motor neuron (SMN) is the cause of the disease [51], but it is possible that loss of functional NAIP may contribute to the severity of the disease. NAIP is reported to inhibit cell death in response to serum withdrawal, menadione and TNF, but because the NAIP cDNA used in these experiments does not correspond to any of the NAIP genes and may represent sequences derived from a number of different NAIP genes, the exact activities of NAIP proteins are unclear.

The strongest evidence for regulation of developmental cell death by IAPs comes from studies in Drosophila, where loss of DIAP1 results in extensive early embryonic cell death and a corresponding increase in caspase activity [52]. An equivalent study in mammals is still required to establish the role of these proteins in mammalian developmental cell death (see Frontiers section). A punctate perinuclear pattern of expression has been described for DIAP2 when overexpressed in insect cells [53].

BIRPs involved in the regulation of cell division

Although originally described as a protein that could inhibit cell death [21], Survivin functions primarily in the regulation of cell division, a role conserved in the yeast and C. elegans BIRPs, whose BIR domains closely resemble that of Survivin [23,24,54,55,56,57,58,59]. Survivin is expressed only during mitosis (see Table 1). Subcellular localization has shown that Survivin is a chromosome passenger protein: that is, it is initially associated with the centromeres, but at the metaphase-anaphase transition it leaves the centromeres and remains in the spindle midzone [56,57,58,60]. It can be found in the mid-body at telophase, after which it is ubiquitinated and degraded. Consistent with its subcellular localization, elimination of Survivin by homologous recombination results in mouse embryos that are unable to survive beyond day 5 because of failure of cytokinesis [56].

The C. elegans proteins BIR-1 and BIR-2 are also involved in the regulation of cytokinesis [23,57]. BIR-1, like Survivin, is expressed only during cell division and is a chromosome passenger protein. The phenotype of BIR-1-deficient embryos is identical to that of embryos deficient for the Aurora-like kinase AIR-2, and BIR-1 is required for localization of AIR-2. Like Survivin and the C. elegans BIRPs, yeast proteins ScBIR1P and Spbir1P have a role in regulating cell division [24], and as yeasts do not have caspases, a role in cell-death regulation can be excluded.

Mammalian Bruce/Apollon has a punctate pattern of cellular expression and colocalizes with the Golgi marker protein TGN38. Expression in dendrites and axons of primary neurons has also been detected [22]. While Bruce has a BIR domain at its amino terminus, it also has ubiquitin-conjugating activity as a result of a ubiquitin-conjugating enzyme (UBC) domain at the carboxyl terminus of the protein. The BIR domain of Bruce is most similar to the BIR domains of Survivin and other BIRPs that are involved in regulating cell division, although the function of Bruce is unknown.

Mechanism of caspase inhibition

Caspases are produced as inactive zymogens that are processed into an active form following cell-death stimuli. The active caspase is believed to be a heterotetrameric complex generated from two zymogen monomers. Cell-death pathways involve the sequential activation of initiator and effector caspases (see Figure 2). Activation of initiator caspases such as caspases 9 and 8 is facilitated by adaptor proteins such as Apaf-1 or FADD, and when activated, caspases 8 and 9 can process and activate downstream effector caspases such as caspases 3 and 7. IAPs can inhibit some active caspases, whereas the mammalian protein DIABLO antagonizes IAP function [61,62,63] (see Figures 2,3).

thumbnailFigure 2. The role of IAPs in the regulation of cell death. Apoptosis induced by TNF or Fas ligand via death receptors (DR) involves adaptor-protein-mediated recruitment and activation of initiator caspases, such as caspase 8 (C8), and the subsequent activation of downstream caspases such as caspase 3 (C3) and 7 (not shown). In cell death induced via stress pathways such as irradiation or drugs, cytochrome c (Cyt c) and DIABLO are released from the mitochondria. Cytochrome c binds to the carboxyl terminus of the adaptor protein Apaf-1, allowing it to unfold, interact with inactive caspase 9 (Pro-C9) and promote its oligomerization and autoprocessing to give active C9; active caspase 9 then can activate downstream caspases. Pro-survival members of the Bcl-2 family inhibit cell death via stress pathways and can prevent release of cytochrome c and DIABLO from mitochondria. The downstream caspases cleave cellular substrates (such as poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated DNase (ICAD)), resulting in many morphological changes and culminating in cell death. IAPs prevent cell death by interacting with and inhibiting active caspases, whereas the IAP antagonist DIABLO can prevent these interactions.

thumbnailFigure 3. Mechanism of caspase inhibition by IAPs and its prevention by the IAP antagonist DIABLO/Smac. (a) The amino terminus of the p10 subunit of caspase 9, revealed following autoprocessing, interacts tightly within a groove of the BIR3 domain of XIAP. (b) The linker region upstream of the BIR2 domain of XIAP interacts tightly with the catalytic site of caspase 3 (and caspase 7; C indicates the catalytic cysteine residue), resulting in effective caspase inhibition. A less significant interaction of the amino terminus of the small subunit of caspase 3 within a groove of the BIR2 domain has been proposed. (c) The amino terminus of DIABLO (red) is similar to that of caspase 9 and competes for the exact same interaction site within the BIR3 domain. (d) A similar groove within the BIR2 domain of XIAP is believed to mediate interaction with DIABLO and provides a mechanism for DIABLO to remove caspase 3 from XIAP.

The BIR3 domain of XIAP interacts with and inhibits active processed caspase 9 [46,63,64]. The amino terminus of DIABLO and that of the p10 subunit of active caspase 9 - which is revealed only after autoprocessing - are similar and compete for exactly the same site within a groove of the BIR3 domain of XIAP [64,65,66,67,68,69] (Figure 3). The interactions of DIABLO and caspase 9 with XIAP are thus mutually exclusive. The amino termini of the Drosophila proteins Grim, Reaper and Hid are similar to the amino terminus of DIABLO within the first four amino acids, and this region is responsible for interaction with IAPs [67,68,69].

The main point of contact between caspases 3 and 7 and XIAP involves the linker region immediately upstream of the BIR2 domain of XIAP [31,32,33,70] (Figure 3). The linker forms a direct contact with the catalytic site of the caspases, thereby blocking their activity. An additional interaction of the amino terminus of the processed p10 fragment of caspase 3 within the groove of the BIR2 domain has been proposed [33] and, although dispensable for caspase interaction and inhibition by XIAP, the IAP antagonist DIABLO/Smac is thought to compete for the same groove, presumably levering out caspase 3 and dislodging it from the IAP.

DIABLO is a dimeric protein with two amino termini that can potentially interact with BIR domains [65]. Although DIABLO is able to interact with individual BIR2 and BIR3 domains, albeit with higher affinity for the BIR3, the type of interaction favored with full-length XIAP is not known. For example, it is possible that a DIABLO dimer interacts simultaneously via its two amino termini with both the BIR2 and BIR3 domains on a single XIAP molecule, or that the two amino termini interact with BIR domains on different XIAP molecules with three different possible BIR domain combinations (two BIR2 domains, a BIR2 plus BIR3 domain or two BIR3 domains). Establishing this structurally may be difficult given that the generation of well-folded full-length XIAP has eluded crystallographers so far.


Our understanding of IAPs and how they inhibit cell death has taken enormous strides in the last few months. At a structural level, we now know how IAPs interact with and inhibit caspases and how this interaction can be regulated by IAP antagonists such as DIABLO. Much research is still required, however, to define the different roles for different mammalian IAP proteins in the face of different cell-death stimuli. It is likely that there is some redundancy between family members. Indeed, MIHA-deficient mice are without phenotype, with the exception of apparently increased expression levels of cIAP-1 and cIAP-2, suggesting some compensation [71]. It may be necessary to generate mice deficient for more than one IAP in order to establish the role of IAPs in mammals. So far, only one mammalian IAP antagonist, DIABLO, has been described, but given that there are three such proteins in Drosophila, other mammalian IAP antagonists are almost certain to exist. The second group of BIRPs discussed in this review are clearly involved in regulating cytokinesis, although the exact mechanism is not known. Direct interactions of BIR domains from these proteins with other cellular proteins have not yet been reported but are likely to provide some clues to how these proteins function.


We would like to acknowledge John Silke for helpful discussions.


  1. Birnbaum MJ, Clem RJ, Miller LK: An apoptosis inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with cys/his sequence motif.

    J Virol 1994, 68:2521-2528.

    The first description of OpIAP.

    PubMed Abstract | PubMed Central Full Text OpenURL

  2. Crook NE, Clem RJ, Miller LK: An apoptosis inhibiting baculovirus gene with a zinc finger like motif.

    J Virol 1993, 67:2168-2174.

    The first description of an IAP; baculoviral CpIAP was identified by its ability to prevent cell death of insect cells transfected with Autographa californica nuclear polyhedrosis virus DNA from which the anti-apoptotic gene p35 had been deleted.

    PubMed Abstract | PubMed Central Full Text OpenURL

  3. Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV: The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral-inhibitor of apoptosis proteins.

    Cell 1995, 83:1243-1252.

    The first description of mammalian cIAP-1 and cIAP-2, identifying them as proteins that interact with the TNF receptor via direct interaction with TRAF1 and TRAF2.

    PubMed Abstract | Publisher Full Text OpenURL

  4. Hay BA, Wassarman DA, Rubin GM: Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death.

    Cell 1995, 83:1253-1262.

    The first description of Drosophila IAPs and demonstration that overexpression of DIAP1 in the fly eye can prevent both normal cell death and that induced by overexpression of the pro-death proteins Reaper and Hid.

    PubMed Abstract | Publisher Full Text OpenURL

  5. Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Chertonhorvat G, Farahani R, Mclean M, Ikeda JE, Mackenzie A, Korneluk RG: Suppression of apoptosis in mammalian cells by NAIP and a related family of IAPgenes.

    Nature 1996, 379:349-353.

    One of the first descriptions of mammalian IAPs cIAP-1, cIAP-2, XIAP and NAIP and of Drosophila DIAP1.

    PubMed Abstract | Publisher Full Text OpenURL

  6. Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL: Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.

    Proc Natl Acad Sci USA 1996, 93:4974-4978.

    One of the first descriptions of mammalian cIAP-1, cIAP-2 and XIAP.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  7. Duckett CS, Nava VE, Gedrich RW, Clem RJ, Vandongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB: A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors.

    EMBO J 1996, 15:2685-2694.

    One of the first descriptions of Drosophila and mammalian IAPs (DIAP1 and XIAP).

    PubMed Abstract OpenURL

  8. You MJ, Ku PT, Hrdlickova R, Bose HR: Ch-iap1, a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-rel oncoprotein.

    Mol Cell Biol 1997, 17:7328-7341.

    A report of an IAP in chickens.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Human Gene Nomenclature Database [] webcite

    Contains information on the new nomenclature for IAPs/BIRPs (BIRC1,2, and so on).

  10. Miller LK: An exegesis of IAPs: salvation and surprises from BIR motifs.

    Trends Cell Biol 1999, 9:323-328.

    A review on the different types of BIR domains and the two emerging functions of BIRPs.

    PubMed Abstract | Publisher Full Text OpenURL

  11. Huang QH, Deveraux QL, Maeda S, Salvesen GS, Stennicke HR, Hammock BD, Reed JC: Evolutionary conservation of apoptosis mechanisms: lepidopteran and baculoviral inhibitor of apoptosis proteins are inhibitors of mammalian caspase-9.

    Proc Natl Acad Sci USA 2000, 97:1427-1432.

    Describes SfIAP, a baculoviral IAP that is highly related to insect IAPs.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  12. Farahani R, Fong WG, Korneluk RG, Mackenzie AE: Genomic organization and primary characterization of miap-3 - the murine homologue of human X-linked IAP.

    Genomics 1997, 42:514-518.

    Description of the murine XIAP gene.

    PubMed Abstract | Publisher Full Text OpenURL

  13. Rajcanseparovic E, Liston P, Lefebvre C, Korneluk RG: Assignment of human inhibitor of apoptosis protein (iap) genes xiap, hiap-1, and hiap-2 to chromosomes Xq25 and 11q22-q23 by fluorescence in situ hybridization.

    Genomics 1996, 37:404-406.

    A chromosomal localization analysis of the human IAP genes.

    PubMed Abstract | Publisher Full Text OpenURL

  14. Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM: ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas.

    Curr Biol 2000, 10:1359-1366.

    This paper and [15,16] describe ML-IAP/LIVIN/BIRC7, a mammalian IAP with a single BIR domain and a RING-finger motif.

    PubMed Abstract | Publisher Full Text OpenURL

  15. Lin JH, Deng G, Huang QH, Morser J: KIAP, a novel member of the inhibitor of apoptosis protein family.

    Biochem Biophys Res Comm 2000, 279:820-831.

    See [14].

    PubMed Abstract | Publisher Full Text OpenURL

  16. Kasof GM, Gomes BC: Livin, a novel inhibitor of apoptosis protein family member.

    J Biol Chem 2001, 276:3238-3246.

    See [14].

    PubMed Abstract | Publisher Full Text OpenURL

  17. Yaraghi Z, Korneluk RG, Mckenzie A: Cloning and characterization of the multiple murine homologues of NAIP (neuronal apoptosis inhibitory protein).

    Genomics 1998, 51:107-113.

    This paper and [18,19] report the six different loci of murine NAIP genes and their various transcripts.

    PubMed Abstract | Publisher Full Text OpenURL

  18. Huang SD, Scharf JM, Growney JD, Endrizzi MG, Dietrich WF: The mouse Naip gene cluster on Chromosome 13 encodes several distinct functional transcripts.

    Mamm Genome 1999, 10:1032-1035.

    See [17].

    PubMed Abstract | Publisher Full Text OpenURL

  19. Yamamoto K, Sakai H, Hadano S, Gondo Y, Ikeda JE: Identification of two distinct transcripts for the neuronal apoptosis inhibitory protein gene.

    Biochem Biophys Res Comm 1999, 264:998-1006.

    See [17].

    PubMed Abstract | Publisher Full Text OpenURL

  20. Roy N, Mahadevan MS, Mclean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besnerjohnston A, Lefebvre C, Kang XL, et al.: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy.

    Cell 1995, 80:167-178.

    The first description of a mammalian NAIP.

    PubMed Abstract | Publisher Full Text OpenURL

  21. Ambrosini G, Adida C, Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma.

    Nat Med 1997, 3:917-921.

    The first description of Survivin, a BIRP with a single BIR domain.

    PubMed Abstract OpenURL

  22. Hauser HP, Bardroff M, Pyrowolakis G, Jentsch S: A giant ubiquitin-conjugating enzyme related to iap apoptosis inhibitors.

    J Cell Biol 1998, 141:1415-1422.

    The first description of Bruce, a large protein with an amino-terminal BIR domain and a UBC motif at the carboxyl terminus.

    PubMed Abstract | Publisher Full Text OpenURL

  23. Fraser AG, James C, Evan GI, Hengartner MO: Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis.

    Curr Biol 1999, 9:292-301.

    The authors observed that worm embryos lacking BIR-1 are unable to complete cytokinesis.

    PubMed Abstract | Publisher Full Text OpenURL

  24. Uren AG, Beilharz T, O'Connell MJ, Bugg SJ, van Driel R, Vaux DL, Lithgow T: Role for yeast inhibitor of apoptosis (IAP)-like proteins in cell division.

    Proc Natl Acad Sci USA 1999, 96:10170-10175.

    Yeast deficient in BIRPs have defects in spore formation and/or division after germination.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  25. Jones G, Jones D, Zhou L, Steller H, Chu YX: Deterin, a new inhibitor of apoptosis from Drosophila melanogaster.

    J Biol Chem 2000, 275:22157-22165.

    First description of Drosophila Deterin, a single BIR-domain-containing protein.

    PubMed Abstract | Publisher Full Text OpenURL

  26. Li FZ, Altieri DC: The cancer antiapoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression.

    Cancer Res 1999, 59:3143-3151.

    Description of the exon structure and promoter of the mouse survivin gene.

    PubMed Abstract | Publisher Full Text OpenURL

  27. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD: Survivin-Delta Ex3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties.

    Cancer Res 1999, 59:6097-6102.

    Two different isoforms of human Survivin differ in the BIR-domain-containing region; Survivin-2B is less anti-apoptotic.

    PubMed Abstract | Publisher Full Text OpenURL

  28. Conway EM, Pollefeyt S, Cornelissen J, DeBaere I, Steiner-Mosonyi M, Ong K, Baens M, Collen D, Schuh AC: Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions.

    Blood 2000, 95:1435-1442.

    Description of mouse survivin gene and evidence for alternative splicing; only two splice forms inhibit caspase 3 activity.

    PubMed Abstract | Publisher Full Text OpenURL

  29. Hinds MG, Norton RS, Vaux DL, Day CL: Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat.

    Nat Struct Biol 1999, 6:648-651.

    The solution structure of cIAP-1 BIR3 domain.

    PubMed Abstract | Publisher Full Text OpenURL

  30. Sun CH, Cai ML, Meadows RP, Xu N, Gunasekera AH, Herrmann J, Wu JC, Fesik SW: NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP.

    J Biol Chem 2000, 275:33777-33781.

    The structure of the BIR3 domain of XIAP reveals that this domain is the minimal region required to inhibit caspase 9.

    PubMed Abstract | Publisher Full Text OpenURL

  31. Chai JJ, Shiozaki E, Srinivasula SM, Wu Q, Dataa P, Alnemri ES, Shi YG: Structural basis of caspase-7 inhibition by XIAP.

    Cell 2001, 104:769-780.

    Describes interaction of caspase 7 with an XIAP peptide comprising 18 amino acids from the linker region upstream of the BIR2 domain.

    PubMed Abstract | Publisher Full Text OpenURL

  32. Huang YH, Park YC, Rich RL, Segal D, Myszka DG, Wu H: Structural basis of caspase inhibition by XIAP: Differential roles of the linker versus the BIR domain.

    Cell 2001, 104:781-790.

    Demonstrates that caspase 7 interaction with XIAP involves the linker region upstream of the BIR2 domain rather than the BIR2 domain itself.

    PubMed Abstract | Publisher Full Text OpenURL

  33. Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun CH, Fesik SW, Liddington RC, Salvesen GS: Structural basis for the inhibition of caspase-3 by XIAP.

    Cell 2001, 104:791-800.

    This paper demonstrates that the main site of caspase 3 interaction with XIAP involves the linker region upstream of BIR2 domain, although an additional interaction of the amino terminus of the small caspase subunit within the DIABLO/Smac-binding pocket of the BIR2 domain is proposed.

    PubMed Abstract | Publisher Full Text OpenURL

  34. Yang Y, Fang SY, Jensen JP, Weissman AM, Ashwell JD: Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.

    Science 2000, 288:874-877.

    Demonstrating that the RING-finger domain of cIAP-1 and XIAP can catalyze self-ubiquitination of IAPs.

    PubMed Abstract | Publisher Full Text OpenURL

  35. Freemont PS: The RING finger. A novel protein sequence motif related to the zinc finger.

    Ann NY Acad Sci 1993, 684:174-192.

    A review of the properties of RING-finger domains.

    PubMed Abstract OpenURL

  36. Barlow PN, Luisi B, Milner A, Elliott M, Everett R: Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy. A new structural class of zinc-finger.

    J Mol Biol 1994, 237:201-211.

    Describing the structure of a RING-finger domain.

    PubMed Abstract | Publisher Full Text OpenURL

  37. Hofmann K, Bucher P, Tschopp J: The card domain - a new apoptotic signalling motif.

    Trends Biochem Sci 1997, 22:155-156.

    First observation of the CARD domain within adaptor proteins, caspases and IAPs.

    PubMed Abstract | Publisher Full Text OpenURL

  38. Chou JJ, Matsuo H, Duan H, Wagner G: Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment.

    Cell 1998, 94:171-180.

    The structure of RAIDD CARD, the first structure of a CARD, is solved and shown to be similar to the Fas death domain.

    PubMed Abstract | Publisher Full Text OpenURL

  39. Qin HX, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi YG: Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1.

    Nature 1999, 399:549-557.

    This paper and [40-42] describe the structure of the Apaf-1 CARD, in the case of [39,40] interacting with the CARD domain from caspase 9.

    PubMed Abstract | Publisher Full Text OpenURL

  40. Zhou P, Chou J, Olea RS, Yuan JY, Wagner G: Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: A structural basis for specific adaptor/caspase interaction.

    Proc Natl Acad Sci USA 1999, 96:11265-11270.

    See [39].

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  41. Vaughn DE, Rodriguez J, Lazebnik Y, Joshua-Tor L: Crystal structure of Apaf-1 caspase recruitment domain: An alpha-helical Greek key fold for apoptotic signaling.

    J Mol Biol 1999, 293:439-447.

    See [39].

    PubMed Abstract | Publisher Full Text OpenURL

  42. Day CL, Dupont C, Lackmann M, Vaux DL, Hinds MG: Solution structure and mutagenesis of the caspase recruitment domain (CARD) from Apaf-1.

    Cell Death Differ 1999, 6:1125-1132.

    See [39].

    PubMed Abstract | Publisher Full Text OpenURL

  43. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE: The inhibitors of apoptosis (IAPs) and their emerging role in cancer.

    Oncogene 1998, 17:3247-3259.

    A review of IAPs and their anti-apoptotic activities.

    PubMed Abstract | Publisher Full Text OpenURL

  44. Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases.

    Nature 1997, 388:300-304.

    The first description of an interaction between an IAP and a caspase.

    PubMed Abstract | Publisher Full Text OpenURL

  45. Takahashi R, Deveraux Q, Tamm I, Welsh K, Assamunt N, Salvesen GS, Reed JC: A single BIR domain of XIAP sufficient for inhibiting caspases.

    J Biol Chem 1998, 273:7787-7790.

    Demonstrates that the region of XIAP encompassing the BIR2 domain is able to inhibit caspases 3 and 7.

    PubMed Abstract | Publisher Full Text OpenURL

  46. Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC: Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases.

    EMBO J 1999, 18:5242-5251.

    Demonstrates that the BIR1-2 fragment is a specific inhibitor of caspase 3, whereas caspase 9 is inhibited by the BIR3-RING fragment.

    PubMed Abstract | Publisher Full Text OpenURL

  47. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K: XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway.

    EMBO J 1999, 18:179-187.

    Describing interactions of XIAP with both TAB1, which lies upstream of a MAP kinase pathway, and the BMP receptor.

    PubMed Abstract | Publisher Full Text OpenURL

  48. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS: NF-kappa-B antiapoptosis - induction of TRAF1 and TRAF 2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.

    Science 1998, 281:1680-1683.

    Levels of cIAP-1 and cIAP-2 increase following NF-κB activation.

    PubMed Abstract | Publisher Full Text OpenURL

  49. Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC: The cIAP-1 and cIAP-2 proteins are direct inhibitors of specific caspases.

    EMBO J 1997, 16:6914-6925.

    Demonstrating that cIAP-1 and cIAP-2 interact with and inhibit caspases 3 and 7.

    PubMed Abstract | Publisher Full Text OpenURL

  50. Mccarthy JV, Dixit VM: Apoptosis induced by Drosophila reaper and grim in a human system - attenuation by inhibitor of apoptosis proteins (cIAPs).

    J Biol Chem 1998, 273:24009-24015.

    Demonstrating the pro-apoptotic effect of Drosophila proteins Reaper and Grim in human cells and inhibition by human IAPs.

    PubMed Abstract | Publisher Full Text OpenURL

  51. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, et al.: Identification and characterization of a spinal muscular atrophy-determining gene.

    Cell 1995, 80:155-165.

    Identifying deletions or mutations of the SMN gene as the primary cause of spinal muscular atrophy.

    PubMed Abstract | Publisher Full Text OpenURL

  52. Wang SL, Hawkins CJ, Yoo SJ, Muller HAJ, Hay BA: The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID.

    Cell 1999, 98:453-463.

    Demonstrates that Hid promotes cell death by preventing inhibition of caspases by DIAP1.

    PubMed Abstract | Publisher Full Text OpenURL

  53. Vucic D, Kaiser WJ, Harvey AJ, Miller LK: Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs).

    Proc Natl Acad Sci USA 1997, 94:10183-10188.

    Drosophila and baculoviral IAPs can prevent Reaper-induced cell death. Their expression results in a shift from cytoplasmic to a punctate perinuclear pattern of Reaper expression, coinciding with the expression pattern of the IAPs.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  54. Li FZ, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin.

    Nature 1998, 396:580-584.

    First evidence for regulation of cell division by BIRPs.

    PubMed Abstract | Publisher Full Text OpenURL

  55. Otaki M, Hatano M, Kobyashi K, Ogasawara T, Kuriyama T, Tokuhisa T: Cell cycle-dependent regulation of TIAP/m-survivin expression.

    Biochim Biophys Acta 2000, 7:188-194.

    Description of murine Survivin and its promoter and regulation.


  56. Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL, Choo KHA: Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype.

    Curr Biol 2000, 10:1319-1328.

    Demonstrating the role of Survivin in the regulation of cytokinesis.

    PubMed Abstract | Publisher Full Text OpenURL

  57. Speliotes EK, Uren A, Vaux D, Horvitz HR: The survivin-like C-elegans BIR-1 protein acts with the aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone.

    Mol Cell 2000, 6:211-223.

    Demonstrating the role of C. elegans BIRPs in regulating cytokinesis.

    PubMed Abstract | Publisher Full Text OpenURL

  58. Skoufias DA, Mollinari C, Lacroix FB, Margolis RL: Human survivin is a kinetochore-associated passenger protein.

    J Cell Biol 2000, 151:1575-1581.

    The authors overexpresed and showed that Survivin is a passenger protein; two mutants failed to localize to the kinetochores.

    PubMed Abstract | Publisher Full Text OpenURL

  59. Li FZ, Flanary PL, Altieri DC, Dohlman HG: Cell division regulation by BIR1, a member of the inhibitor of apoptosis family in yeast.

    J Biol Chem 2000, 275:6707-6711.

    Disruption of Spbir1p shows that BIRPs have a role in regulating cell division in Schizosaccharomyces pombe.

    PubMed Abstract | Publisher Full Text OpenURL

  60. O'Connor DS, Grossman D, Plescia J, Li FZ, Zhang H, Villa A, Tognin S, Marchisio PC, Altieri DC: Regulation of apoptosis at cell division by p34(cdc2) phosphorylation of survivin.

    Proc Natl Acad Sci USA 2000, 97:13103-13107.

    Survivin interacts with and is phosphorylated by the p34(cdc2)-cyclin B1complex.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  61. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.

    Cell 2000, 102:43-53.

    The first description (with [62]) of a mammalian IAP antagonist also known as DIABLO or Smac.

    PubMed Abstract | Publisher Full Text OpenURL

  62. Du CY, Fang M, Li YC, Li L, Wang XD: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.

    Cell 2000, 102:33-42.

    See [61].

    PubMed Abstract | Publisher Full Text OpenURL

  63. Ekert PG, Silke J, Hawkins CJ, Verhagen AM, Vaux DL: DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9.

    J Cell Biol 2001, 152:483-490.

    Demonstrating direct competition between DIABLO and caspase 9 for interaction with XIAP.

    PubMed Abstract | Publisher Full Text OpenURL

  64. Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee R, Robbins PD, Fernandes-Alnemri T, Shi Y, Alnemri ES: A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.

    Nature 2001, 410:112-116.

    The amino terminus of the small subunit of processed caspase 9 and the amino terminus of mature DIABLO are similar and compete for the same interaction site within the BIR3 domain of XIAP.

    PubMed Abstract | Publisher Full Text OpenURL

  65. Chai JJ, Du CY, Wu JW, Kyin S, Wang XD, Shi YG: Structural and biochemical basis of apoptotic activation by Smac/DIABLO.

    Nature 2000, 406:855-862.

    Describes the structure of DIABLO and demonstrates that DIABLO is a dimeric protein that interacts with IAPs through its amino terminus.

    PubMed Abstract | Publisher Full Text OpenURL

  66. Srinivasula SM, Datta P, Fan XJ, Fernandes-Alnemri T, Huang ZW, Alnemri ES: Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway.

    J Biol Chem 2000, 275:36152-36157.

    Determines that the amino terminus of DIABLO is responsible for interaction with IAPs.

    PubMed Abstract | Publisher Full Text OpenURL

  67. Liu ZH, Sun CH, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW: Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.

    Nature 2000, 408:1004-1008.

    Describing the solution structure of the XIAP BIR3 domain interacting with a nine-amino-acid peptide corresponding to the amino terminus of mature DIABLO.

    PubMed Abstract | Publisher Full Text OpenURL

  68. Wu G, Chai JJ, Suber TL, Wu JW, Du CY, Wang XD, Shi YG: Structural basis of IAP recognition by Smac/DIABLO.

    Nature 2000, 408:1008-1012.

    The crystal structure of DIABLO complexed with the BIR3 domain of XIAP.

    PubMed Abstract | Publisher Full Text OpenURL

  69. Silke J, Verhagen AM, Ekert PG, Vaux DL: Sequence as well as functional similarity for DIABLO/Smac and Grim, Reaper and Hid?

    Cell Death Differ 2000, 7:1275.

    Observation that the amino terminus of mature DIABLO is similar to the amino terminus of the Drosophila IAP antagonists Grim, Reaper and Hid.

    PubMed Abstract | Publisher Full Text OpenURL

  70. Silke J, Ekert PG, Day CL, Hawkins CJ, Baca M, Chew J, Pakusch M, Verhagen AM, Vaux DL: Direct inhibition of caspase 3 is dispensible for the anti-apoptotic activity of XIAP.

    EMBO J 2001, 20:3114-3123.

    Demonstrates the importance of residues within the linker region upstream of the BIR2 domain in XIAP inhibition of caspase 3.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  71. Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB: Characterization of XIAP-deficient mice.

    Mol Cell Biol 2001, 21:3604-3608.

    XIAP-deficient mice develop normally, with the only observed change being increased levels of cIAP-1 and -2 expression.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  72. PHYLIP:PHYLIP Phylogeny Inference Package [] webcite

    Program used to generate the phylogenetic tree of IAPs (Figure 2).