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
]. Cellular IAPs were subsequently described in insects and vertebrates [3
]. 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 , and the relationship of different BIR domains to each other is illustrated by the phylogenetic tree in Figure and an alignment of a selection of BIR domains is given in Figure . Table 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.
Figure 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 (more ...)
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 ). 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.
]). 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
There are thought to be six tightly linked NAIP
genes in mice and humans [17
]. The BIR domains of NAIPs are more distantly related to the BIR domains of the other mammalian IAPs (see Figure ) and NAIPs do not have a RING-finger domain but do have a nucleotide-binding domain at their carboxyl terminus [5
]. 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
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 ), yeast Spbir1P and ScBIR1P and Drosophila
proteins d-Bruce and Deterin [21
]. 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 ) 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