The Activator of Apoptosis Smac-DIABLO Acts as a Tetramer in Solution

Mastrangelo, Eloise; Vachette, Patrice; Cossu, Federica; Malvezzi, Francesca; Bolognesi, Martino; Milani, Mario

doi:10.1016/j.bpj.2014.11.3471

Cited by 15 publications

(23 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6). In most cases such interactions take place between two copies of the involved domains of XIAP and the relative partners, as is the case for the BIR1-TAB (Lu et al, 2007) and BIR2caspase-3/7 complexes (Riedl et al, 2001;Scott et al, 2005), which are dimeric in the crystallographic structure, and the BIR2-BIR3-Smac/DIABLO complex, where it has been proposed that a Smac/DIABLO tetramer binds two BIR2-BIR3 pairs (Wu et al, 2000;Huang et al, 2003;Mastrangelo et al, 2015). By comparing our model [ Fig.…”

Section: Resultsmentioning

confidence: 98%

See 1 more Smart Citation

Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach

Polykretis

Luchinat

Bonucci

et al. 2019

Int Union Crystallogr J

View full text Add to dashboard Cite

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has therefore become an important target for the treatment of malignancy. Despite the fact that the structure of each single domain is known, the conformation of the full-length protein has never been determined. Here, the first structural model of the full-length XIAP dimer, determined by an integrated approach using nuclear magnetic resonance, small-angle X-ray scattering and electron paramagnetic resonance data, is presented. It is shown that XIAP adopts a compact and relatively rigid conformation, implying that the spatial arrangement of its domains must be taken into account when studying the interactions with its physiological partners and in developing effective inhibitors.

show abstract

Section: Resultsmentioning

confidence: 98%

“…(c) Two BIR3 domains in complex with a Smac/DIABLO dimer (PDB entry 1g73; Wu et al, 2000). (d) Two BIR2-BIR3 constructs in complex with a Smac/DIABLO tetramer based on a SAXS-derived model (Mastrangelo et al, 2015). XIAP domains are labelled with the initial letter of each name; inter-cysteine distances are shown in (a), (b) and (c).…”

Section: Discussionmentioning

confidence: 99%

Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach

Polykretis

Luchinat

Bonucci

et al. 2019

Int Union Crystallogr J

View full text Add to dashboard Cite

show abstract

“…Once in the cytosol, Smac/Diablo undergoes maturation with the cleavage of its N-terminal 55 amino acids. The loss of this sequence allows the exposure of the conserved IBM, present also in caspases and responsible for the interaction with the IAP BIRs [ [40] , [41] , [42] ] ( Fig. 1 ).…”

Section: Mimicking the Iap Natural Antagonist Smac/diablomentioning

confidence: 99%

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

Cossu

Milani

Mastrangelo

et al. 2019

Computational and Structural Biotechnology Journal

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Apoptosis plays an important role in normal cell development and tissue homeostasis (Joza et al, 2001;Danial and Korsmeyer, 2004), and dysregulated apoptosis is associated with many pathological conditions (Lawen, 2003), such as Alzheimer's disease (Yuan and Yankner, 2000;LeBlanc, 2005), Parkinson's disease (Wang et al, 2016), and cancer (Oltersdorf et al, 2005). Mitochondria promote apoptosis by releasing Cytochrome (CYTC), Diablo homolog (DIABLO) (Mastrangelo et al, 2015), AIF (Li et al, 2003), ENDOG (Dupont-Versteegden et al, 2006), and other bioactive substances. Mitochondrial apoptosis pathways are either caspase-dependent or -independent (Pinkoski et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Expression profiles of genes associated with mitochondria-mediated apoptosis and their roles in liver regeneration

Xing¹,

Li²,

Guo³

et al. 2016

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Mitochondria are closely associated with cell survival, and it is of interest to determine whether apoptosis pathways, which are mediated by mitochondria, are involved in liver regeneration (LR). To identify the mechanisms underlying mitochondria-mediated apoptosis during rat LR, we used the Rat Genome 230 2.0 Array to investigate changes in gene expression. Next, we searched the GO and NCBI databases for genes associated with apoptosis mediated by mitochondria, and QIAGEN and KEGG databases for any related signaling pathways. The expression profile function (Et) was then used to calculate the activity level of known signaling pathways associated with apoptosis. The results revealed the expression of 436 genes associated with apoptosis signaling pathways, among which 152 were confirmed to be primarily related to LR. Overall, 99, 136, 95, and 91 genes were first expressed during the initiation [0.5-4 h after partial hepatectomy (PH)], G0/G1 transition (4-6 h after PH), cell proliferation (6-66 h after PH), and redifferentiation and structural reconstruction (66-144 h after PH) phases, demonstrating that LR-related genes were primarily induced in the initiation phase, and were then expressed across multiple phases. Analysis using the gene synergy formula (Et) showed that caspase-dependent and DNA fragment-related/unrelated pathways induced apoptosis in the early and late periods of LR, and the caspase-independent and DNA fragment-related/unrelated pathways almost in the whole process. Therefore, these results show that several apoptosis pathways regulate LR in rat.

show abstract

The Activator of Apoptosis Smac-DIABLO Acts as a Tetramer in Solution

Cited by 15 publications

References 42 publications

Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach

Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach

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

Expression profiles of genes associated with mitochondria-mediated apoptosis and their roles in liver regeneration

Contact Info

Product

Resources

About