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Review
, 7 (10), 988-94

Human Inhibitor of Apoptosis Proteins: Why XIAP Is the Black Sheep of the Family

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Review

Human Inhibitor of Apoptosis Proteins: Why XIAP Is the Black Sheep of the Family

Brendan P Eckelman et al. EMBO Rep.

Abstract

Several of the inhibitor of apoptosis protein (IAP) family members regulate apoptosis in response to various cellular assaults. Some members are also involved in cell signalling, mitosis and targeting proteins to the ubiquitin-proteasome degradation machinery. The most intensively studied family member, X-linked IAP (XIAP), is a potent inhibitor of caspase activity; hence, it is generally assumed that direct caspase inhibition is an important conserved function of most members of the family. Biochemical and structural studies have precisely mapped the elements of XIAP required for caspase inhibition. Intriguingly, these elements are not conserved among IAPs. Here, we review current knowledge of the caspase-inhibitory potential of the human IAPs and show that XIAP is probably the only bona fide caspase inhibitor, suggesting that the other family members never gained the ability to directly inhibit caspase activity.

Figures

Figure 1
Figure 1
Schematic representation of the human inhibitor of apoptosis protein family. In addition to at least one baculoviral IAP repeat (BIR) domain, most IAPs have other distinct functional domains. The really interesting new gene (RING) domain found in many IAPs is an E3 ligase that presumably directs targets to the ubiquitin-proteasome degradation system. Caspase-recruitment domains (CARDs) can mediate homotypic protein–protein interactions, although the binding partners for the cellular IAP (cIAP) CARDs have not yet been elucidated. Bruce has a ubiquitin-conjugation (UBC) domain that is found in many ubiquitin-conjugating enzymes. The NACHT domain of neuronal apoptosis-inhibitory protein (NAIP) resembles a nucleotide-oligomerization domain related to the AAA+ NTPases, whereas the leucine-rich repeats (LRRs) are similar to those of the Toll-like receptors that function as pathogen sensors. BIRC, baculoviral IAP-repeat-containing; HIAP, human IAP; IAP, inhibitor of apoptosis protein; ILP, IAP-like protein; KIAP, kidney IAP; MIH, mammalian IAP homologue; ML-IAP, melanoma IAP; NACHT, domain found in NAIP, CIITA, HET-E and TP-1; Ts-IAP, testicular IAP; XIAP, X-linked IAP.
Figure 2
Figure 2
The caspase-binding elements of human inhibitor of apoptosis proteins. Alignment of baculoviral IAP repeat (BIR) domains with the highest identity. (A) IAP-binding motif (IBM)-interacting groove exosite. The residues that line this groove are highlighted; those identical to XIAP BIR2 or XIAP BIR3 are shown in purple and cyan, respectively. The BIR3 of cIAPs, the BIR2 of neuronal apoptosis-inhibitory protein (NAIP) and the single BIR of ML-IAP share some features of both BIR2 and BIR3 of XIAP. (B) Executioner caspase-inhibitory peptide strand of XIAP that lies at the amino terminus of the BIR2 domain. Crucial residues are shown in green. (C) The helix distal to XIAP BIR3 targets the dimer interface of caspase-9. Crucial residues are shown in red. (D) Crystal structure of BIR2 (right, from Protein Data Bank (PDB) 1I3O) and BIR3 (left, from PDB 1NW9) from XIAP. The executioner caspase-inhibitory element is shown in green, whereas the caspase-9-inhibitory distal helix is shown in red. The IBM-interacting grooves of BIR2 and BIR3 are shown in purple and cyan, respectively. (E) Alignment of XIAP BIR3 with ILP2 showing the truncated amino terminus of the latter. cIAP, cellular IAP; IAP, inhibitor of apoptosis protein; ILP2, IAP-like protein 2; ML-IAP, melanoma IAP; XIAP, X-linked IAP.
Figure 3
Figure 3
Two-site binding mechanisms for protease inhibition. The colour coding is as follows: the inhibitors are shown in green with the co-ordinating zinc in purple, the protease large subunit is shown in blue with the catalytic residue in yellow and the small subunit is shown in grey. (A) X-linked IAP (XIAP) baculoviral IAP repeat 2 (BIR2) complex with caspase-3 (Protein Data Bank (PDB) 1I3O). The amino-terminal peptide strand preceding the BIR2 domain binds across the substrate-binding site, whereas the IAP-binding motif (IBM) of a caspase-3 small subunit, in an adjacent asymmetric unit, docks in the IBM-interacting groove. The mechanism of inhibition is steric occlusion of the active site. (B) XIAP BIR3 complex with a caspase-9 monomer (PDB 1NW9). The IBM of caspase-9 docks into the IBM-interacting groove of BIR3, facilitating interactions of the carboxy-terminal BIR3 helix with the dimer interface of caspase-9. This prevents dimerization or induces monomerization of caspase-9 with concomitant collapse of the active site. (C) Hirudin complex with thrombin (PDB 1HRT). The substrate-binding site is blocked, whereas the carboxy terminus docks to exosite I of thrombin.
None
Brendan P. Eckelman, Fiona L. Scott & Guy S. Salvesen

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