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Review
. 2019 Jan 25:17:142-150.
doi: 10.1016/j.csbj.2019.01.009. eCollection 2019.

Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment

Federica Cossu  1 , Mario Milani  1   2 , Eloise Mastrangelo  1   2 , Daniele Lecis  3
Affiliations
Review

Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment

Federica Cossu et al. Comput Struct Biotechnol J. .

Abstract

Inhibitor of apoptosis (IAP) proteins are characterized by the presence of the conserved baculoviral IAP repeat (BIR) domain that is involved in protein-protein interactions. IAPs were initially thought to be mainly responsible for caspase inhibition, acting as negative regulators of apoptosis, but later works have shown that IAPs also control a plethora of other different cellular pathways. As X-linked IAP (XIAP), and other IAP, levels are often deregulated in cancer cells and have been shown to correlate with patients' prognosis, several approaches have been pursued to inhibit their activity in order to restore apoptosis. Many small molecules have been designed to target the BIR domains, the vast majority being inspired by the N-terminal tetrapeptide of Second Mitochondria-derived Activator of Caspases/Direct IAp Binding with Low pI (Smac/Diablo), which is the natural XIAP antagonist. These compounds are therefore usually referred to as Smac mimetics (SMs). Despite the fact that SMs were intended to specifically target XIAP, it has been shown that they also interact with cellular IAP-1 (cIAP1) and cIAP2, promoting their proteasome-dependent degradation. SMs have been tested in combination with several cytotoxic compounds and are now considered promising immune modulators which can be exploited in cancer therapy, especially in combination with immune checkpoint inhibitors. In this review, we give an overview of the structural hot-spots of BIRs, focusing on their fold and on the peculiar structural patches which characterize the diverse BIRs. These structures are exploited/exploitable for the development of specific and active IAP inhibitors.

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Figures

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Graphical abstract
Fig. 1
Fig. 1
Smac/Diablo and SMs target homologous IAPs involved in different cellular pathways. IAPs are composed of three BIR domains (BIR1 to BIR3), an ubiquitin-associated (UBA) domain and a C-terminal RING domain. cIAPs additionally contain a CARD domain. (A) XIAP inhibits initiator (Caspase-9, green surface) and effector caspases (Caspase-3 and -7, magenta surface), through the interaction of its type II BIRs (BIR3 and BIR2, respectively), represented with grey boxes and surfaces. In particular, type II BIRs display a conserved IBM groove (blue region in the zoomed view), which hosts the N-terminal IAP-binding motif (IBM) reported in spheres. Smac/Diablo released from mitochondria upon stress stimuli, displaces caspases by exposing the N-terminal tetrapeptide AVPI (orange spheres), the base for SM design. (B) cIAPs are present in the cytosol as inactive monomers (panel B, on top). SM treatment induces dimerization and rapid auto-ubiquitination of cIAPs, leading to their degradation. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
The BIR domains: from the primary to the tertiary structure. (A) The sequence alignment of BIRs from cIAP1, cIAP2 and XIAP shows conserved motifs (highlighted in red when fully conserved, written in red when partially conserved), both among different BIRs of the same IAPs (Type I BIR1, compared to Type II BIR2 and BIR3) and among the same BIRs of different IAPs homologues (i.e. the BIR3 of cIAP1, cIAP2 and XIAP). The corresponding secondary structures are reported in green (cIAP1-BIR3 as a reference for Type II BIRs) and in grey (XIAP-BIR1 as reference for Type I BIRs). The alignment was performed with ESPRIPT (http://espript.ibcp.fr) [122]. (B) Structural “hot-spots” on BIRs stabilizing the BIR fold. Beyond the Zinc binding patch (residues in green, Zinc atom in purple), the second hot spot (residues in light blue) involves the fully conserved residues (highlighted in red in the sequences alignment) in the η1-α1-α2-β1-β2 elements. The third hot spot is stabilized by V279, L284, D296, C209 and W310 in orange sticks (Reference structure: cIAP1-BIR3, PDB id: 3MUP [123]). The secondary structure elements (cyan helices, red sheets and magenta loops) in the 3D structure are more clearly reported in the box, together with the location of the hot-spots. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Structural features of the IBM groove of type II BIRs hosting the tetrapeptide AVPI. Electrostatic surfaces (±70 keV) of cIAP1-BIR3 (PDB id: 3D9U), XIAP-BIR3 (PDB id: 1G73) and XIAP-BIR2 (PDB id: 4J46). The IBM groove runs from the negatively charged N-terminal binding cavity (NBC) to the positively charged C-terminal binding cavity (CBC), separated by the conserved Leucine 207/307 (in BIR2/BIR3, respectively). In XIAP-BIR2 the CBC is shallower than in BIR3 due to the interaction between Q197 and K206 (magenta hatches). On the bottom, a zoomed view of the IBM groove of each BIR domain, with the residues interacting with AVPI (in cyan sticks) highlighted in orange, magenta and green sticks, for cIAP1-BIR3, XIAP-BIR3 and XIAP-BIR2, respectively. Structures drawn with PyMOL (https://pymol.org/2/ The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
The surfaces of type I BIRs mediating pro-survival macromolecular complexes. The chain D from 3M0A (cIAP2-BIR1 in complex with TRAF2) was superimposed to chain B from 2POP (XIAP-BIR1 in complex with TAB1), and therefore the two panels (A, B) display the BIR1 molecules in the same orientation. (A) The structure of cIAP2-BIR1 (grey surface) in complex with TRAF2 (yellow cartoon) reveals that the interaction of TRAF2 with the BIR1 domain occurs trough a set of aminoacids (orange area on BIR1) opposite to the surface homologous to the IBM groove (light blue area) of type II BIRs. (B) The orange patch of XIAP-BIR1 (grey surface) interacting with TAB1 (green cartoon) is the same observed for cIAP2-BIR1. The light blue area on XIAP-BIR1 is homologous to the IBM groove found on type II BIRs, but rather than binding to caspases or Smac/DIABLO, is involved in XIAP-BIR1 dimerization. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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