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Keywords:

  • baculovirus IAP repeat (BIR);
  • BIR-containing (BIRC) proteins;
  • inhibitors of apoptotic proteins (IAPs)

Abstract

  1. Top of page
  2. Abstract
  3. Structure of BIR Proteins
  4. Conclusion
  5. Declaration
  6. References
  7. Author Information

Inhibitors of apoptotic proteins (IAPs) can play an important role in inhibiting apoptosis by exerting their negative action on caspases (apoptotic proteins). There are eight proteins in this family: NAIP/BIRC1/NLRB, cellular IAP1 (cIAP1)/human IAP2/BIRC2, cellular IAP2 (cIAP2)/human IAP1/BIRC3, X-linked IAP (XIAP)/BIRC4, survivin/BIRC5, baculoviral IAP repeat (BIR)-containing ubiquitin-conjugating enzyme/apollon/BIRC6, livin/melanoma-IAP (ML-IAP)/BIRC7/KIAP, and testis-specific IAP (Ts-IAP)/hILP-2/BIRC8. Deregulation of these inhibitors of apoptotic proteins (IAPs) may push cell toward cancer and neurodegenerative disorders. Inhibitors of apoptotic proteins (IAPs) may provide new target for anticancer therapy. Drugs may be developed that are inhibiting these IAPs to induce apoptosis in cancerous cells.

The problem of resistance and tolerance to the existing drugs has created a decreased efficacy of these drugs in use. This problem has been tried to be overcome by increasing the drug delivery to the target site by the use of polymers [1, 2] or through nanotechnology [3, 4], synthesis of new drugs, either by the use of proteomics [5], or synthesis from lactic acid bacteria [6], or marine micro-organisms [7]. A large numbers of drugs are constantly being invented for their possible pharmacological value particularly for their antiinflammatory [8], hypotensive [9], hepatoprotective [10], hypoglycemic, amoebicidal, antifertility, cytotoxic, antibiotic [11], spasmolytic [12], bronchodilator, antioxidant [13], antidiarrheal [14], and anti-Parkinsonism properties. Similarly, as cancer is the major cause of death in humans, new targets are being investigated for cytotoxic drug development.

Inhibitors of apoptotic proteins (IAPs) were identified in baculovirus and have baculovirus IAP repeat (BIR) domain. First IAP, OpIAP was recognized from a baculovirus strain in 1993 by Miller and co-workers [15]. Many IAP homologs inhibit apoptosis, but not all the IAPs establish cell death, but directly cause apoptosis regulation [16]. All IAPs have one or more zinc-finger motifs called baculovirus IAP repeats (BIRs), the complete family specifically termed BIR-containing proteins (BIRPs or BIRC proteins) in spite of IAPs. Inhibitors of apoptotic proteins (IAPs) are given in Table 1.

Table 1. Inhibitors of apoptotic proteins (IAPs)
Gene proteinSynonyms
BIRC1NAIP
BIRC2cIAP1
BIRC3cIAP2
BIRC4XIAP (ILP1)
BIRC5Survivin
BIRC6Bruce (Appolon)
BIRC7ML-IAP (livin), (K-IAP)
BIRC8ILP2 (TsIAP)

Structure of BIR Proteins

  1. Top of page
  2. Abstract
  3. Structure of BIR Proteins
  4. Conclusion
  5. Declaration
  6. References
  7. Author Information

Inhibitors of apoptotic proteins (IAPs) inhibit caspase endogenously that are highly conserved throughout evolution from Drosophila to vertebrates [17]. There are eight proteins in this family, which are protein (NAIP/BIRC1/NLRB), cellular IAP1 (cIAP1)/human IAP2/ BIRC2, cellular IAP2 (cIAP2)/human IAP1/BIRC3, X-linked IAP (XIAP)/BIRC4, survivin/BIRC5, baculoviral IAP repeat (BIR)-containing ubiquitin-conjugating enzyme/apollon/BIRC6, livin/melanoma-IAP (ML-IAP)/BIRC7/KIAP, and testis-specific IAP (Ts-IAP)/hILP-2/BIRC8 (Figure 1). There is at least one BIR domain that is required for their classification as IAPs. There is 70- to 80-amino-acid-long motif in BIR domain that is related to their initial discovery in baculovirus, as indicated by the name [18]. There are three BIR domains at amino-terminal portion of mammalian IAPs, XIAP, cIAP1, and cIAP2 [19]. Along with BIR motif, all IAP proteins except survivin have other functional domain, that is, the really interesting new gene (RING) and the caspase-activating and recruitment domain (CARD). The RING domain has E3 ubiquitin ligase activity and regulates proteosomal degradation and ubiquitination of substrates. Auto- or hetero-ubiquitination of IAP proteins mediated with RING domain in regulatory loop or other substrates are degraded, for example, Smac and caspases. Protein–protein interactions are mediated by CARD domain that cause oligimerization with other proteins which have CARD and others which are involved in cell death regulation. Along with mammalian IAP proteins, XIAP has most potent antiapoptotic properties. BIR domain mediates protein–protein interactions but also has deep peptide-binding groove that helps in specific binding. BIR domains are classified in to type 1 and type 2 domains, peptide-binding groove is absent in type 1 BIR domain or only superficial pocket is present. N-terminal tetra-peptide called IAP−binding motifs (IBMs) are present in type 2 domain. IAPs such as XIAP, cIAP1, cIAP2, and Drosophila melanogaster IAP1 (DIAP1) and DIAP2 are regulatory IAPs and have two such types of BIR domains. Caspases or IAP antagonists cannot bind with these domains and interact with these proteins differently. As cIAPs which is type 1 binds with tumor necrosis factor receptor (TNFR)−associated factor 1 (TRAF1) and TRAF2, while BIR1 of XIAPs show interaction by transforming growth factor−β (TgFβ)−activated kinase (TAK1)-binding protein. Binding of N-terminal tetra-peptide called IAP-binding motif (IBMs) through hydrophobic cleft. There are two types of such BIR domains in regulatory apoptosis IAPs such as XIAP, cIAP1, cIAP2, and Drosophila melanogaster IAP1 (DIAP1) and DIAP2 [20, 21]. BIR proteins, BIRC1,2,3,4,7,8 act on caspases and BIRC5,6 and BIR-containing yeast and C. elegens act on cytokinin and mitotic spindle formation to inhibit apoptosis (Figure 2).

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Figure 1. Inhibitor of apoptotic protein (IAP) family (BIR, baculovirus IAP repeats; CARD, caspase-activating and recruitment domain; RING, really interesting new gene).

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Figure 2. BIR proteins, BIRC1,2,3,4,7,8 act on caspases and BIRC5,6 and BIR-containing yeast and C. elegens act on cytokinin and mitotic spindle formation to inhibit apoptosis.

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BIRC1

Synonyms: Baculoviral IAP repeat-containing protein 1 (BIRC1), NAIP.

The neuronal apoptosis inhibitory protein (NAIP), or BIRC1, was first discovered during spinal muscular atrophy due to positional cloning of contestant gene [22]. Five to seven BIRC1 genes were identified depending on strains during amplification of BIRC1 locus in mouse strain. Individual gene in BIRC1 has its own function, suggested in recent research. Resistance to Legionella pneumophila infection is due to BIRC1e, mapped to the Lgn1 locus [23]. BIRC1a does not possess above function. While BIRC1a knockout mice show increased neuronal death during their exposure to kainic acid [24]. BIRC1 show activity by binding with caspase 3, 7, and 9 in the presence of ATP, either it can inhibit enzyme activity or not is unclear [25, 26]. BIR domain present in BIRC1 binds to caspases, and oligomerization domain is NACHT which helps in assembling signaling components. Protein–protein interaction domain is LRR domain which helps in pathogen sensing, but exact mechanism of apoptosis by BIRC1 is not clear [27-29], functions of BIRC1 are that they prevent apoptosis of motor neurons, tissue specificity is only in motor neurons but not in sensory neurons, localized in placenta and liver [30] but less significantly in spinal cord (Figure 3).

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Figure 3. Different micro-organisms via caspases pathway show inhibition of apoptosis.

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BIRC2

Synonyms: Baculoviral IAP repeat-containing protein 2 (BIRC2), C-IAP1, IAP homolog B (IAP-2, hIAP-2, hIAP2), Inhibitor of apoptosis protein 2 RING finger protein 48, TNFR2-TRAF signaling complex protein 2 API1, IAP2, MIHB, BIRC2 contains 3 BIR repeats, 1 CARD domain and 1 RING-type zinc finger motif.

BIRC2 has many functions along with caspase regulation and apoptosis, helps in inflammatory as well as mitogen kinase signaling, immunity, cell proliferation cell invasion, and metastasis. It regulates NF-kappa-B signaling by canonical and non-canonical pathway by E3 ubiquitin–protein ligase. It acts as constitutive suppressor of non-canonical NF-kappa-B signaling pathway and constructive positive regulator of the canonical pathway. E3 ubiquitin–protein ligase activity is mediated by: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, AP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, and MXD1/MAD1 proteins. NEDD8 conjugation pathway, neddylation and inactivation are mediated by an E3 ubiquitin–protein ligase by acting on caspases. Innate immune signaling is regulated by Toll-like receptors (TLRs), Nod-like receptors (NLRs), and RIG-I-like receptors (RLRs), named as pattern recognition receptors (PRRs). A large multiprotein complex ripoptosome that kill cancer cells in a caspase-dependent and caspase-independent manner is protected by BIRC2. Ripoptosome formation is suppressed by ubiquitinating RIPK1 and CASP8. Transcriptional activity of E2F1 can be stimulated. BIRC2 has CARD domain, which by inhibiting RING domain dimerization and E2 ubiquitin donor binding and activation helps in enzyme regulation. Autoinhibition of the E3 ubiquitin–protein ligase is mediated by CARD domain, which suppresses migration and cell proliferation. Stability of BIRC2/c-IAP1 is regulated by USP19 by preventing its ubiquitination. Apoptotic suppressor activity is inhibited by interactions with DIABLO/SMAC and with PRSS25. Also interact with TRAF2 via BIR domains and E2F1, RIPK1, RIPK2, RIPK3, RIPK4, BIRC5/survivin, and USP19. BIRC2 is found in nucleus and cytoplasm [31]. Its nuclear localization is mediated by BIR domain. BIRC2/c-IAP1, CARD domain helps in protein stabilization and of E3 ubiquitin–protein ligase activity inhibition by preventing dimerization of RING domain and binding and activation of E2 ubiquitin donor.

BIRC3

Synonyms: Baculoviral IAP repeat–containing 3 (BIRC3), apoptotic inhibitor 2, c-IAP2, cIAP2, hiap1, inhibitor of apoptotic protein 1, MALT2, mammalian IAP homolog C (MIHC), RNF49, TNFR2-TRAF signaling complex protein.

Action of BIRC3 (NF-κB) by transcriptional factor dimmers (which have combination of p50, p52, c-Rel, p65/RelA, and RelB) in normal cells, these dimmers are in inactive form found in cytoplasm because of interactions of dimmers of NF-κB with IκB inhibitors. NF-κB is activated through extracellular signals of membrane-bound receptors and modulator and adaptor proteins, and as a result of proteasome-mediated degradation of IκB induces nuclear translocation of NF-κB. Degradation of IκB which is proteosomal is mediated by phosphorylation of IκB, by an IκB kinase (IKK) complex. There are two main pathways of NF-κB: a canonical pathway and a non-canonical pathway (Figure 4). There is overlap in these pathways, at cytoplasmic effector proteins many signals at NF-κB pathways, which are being used by both pathways. Canonical pathway is activated by p50–p65 complexes as a result of degradation of coupled IκB, and non-canonical pathway is by dispension of dormant p100-RelB dimer to active p52-RelB due to degradation of IκB C-terminal sequences of NF-κB2 p100. Proteosomal inhibitors can block NF-κB pathways, which by inhibiting degradation of IκB proteins that interrupt NF-κB signaling. From different studies, it is revealed that MM cell lines have nuclear NF-κB activity and blockers of NF-κB signaling can inhibit growth of these NF-κB-positive MM cell lines (e.g., bortezomib, the proteasome inhibitor has much clinical efficacy for MM, which is largely due to anti-NF-κB signaling activity of bortezomib. Function as apoptotic suppressor. The BIR motifs region interacts with TNF receptor–associated factors 1 and 2 (TRAF1 and TRAF2) to form a heteromeric complex, which is then recruited to the tumor necrosis factor receptor 2 (TNFR2). Baculoviral IAP repeat-containing protein 3 has been shown to interact with TRAF1, TRAF2, RIPK1, Caspase-9 and UBE2D2 [21].

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Figure 4. BIRC3 signaling pathway; mutations are shown in multiple myeloma by canonical and non-canonical pathway. By this NF-κB, DNA binding and target gene expression are activated. Arrows show activation whereas – sign show inhibition.

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BIRC4

Synonyms: Baculoviral IAP repeat-containing protein 4 (BIRC4), XIAP-associated factor 1, BIRC4-binding protein (BIRC4BP), XIAPAF1, API3, IAP3.

XIAP is the member of IAP family, which is most widely studied, found on X chromosome. The only IAP, BIRC4 can inhibit caspases enzymatic activity. BIRC4 causes inhibition of apoptosis by binding to TNF-alpha receptors-associated factor TRAF1 and TRAF2, and apoptosis is inhibited which is induced by menadione, a potent free radical inducer as well as interleukin-1-beta-converting enzyme. It has BIR and RING finger domain. It can be expressed in cell lines of mammals and can cause virally induced apoptosis blockade. XIAP is a most potent apoptotic suppressor protein can inhibit cell death proteases by binding with at least two members of caspases, mostly caspase 3 and 7 (Figure 5). BIRC4 has many functions and act on caspases and inhibit apoptosis, also act as immunity and inflammatory signaling, mitogenic kinase signaling, copper homeostasis, cell division, and metastasis. It is located in nucleus and cytoplasm and found in adult person's carcinoma cell lines heart, placenta, lung, lymph node, spleen, and ovary [32, 33].

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Figure 5. Mechanism of action of BIRC4 through caspases pathway. Healthy cells contain caspases in their uncleaved and inactive state (1) Mitochondria releases cytochrome C (Cyt C), which binds with ATP and Apaf-1 (2), apaf-1 binds with caspase 9 and activate it (3), activated caspase 9 causes cleavage and activation of caspase 3 (4), (7) BIRC4 present in the cytosol in sufficient amount binds with activated caspase 9 (5) and inhibits the activation of caspase 3 by caspase 9. As shown in this model, mitochondria releases Diablo\smac dimmers which make complex with BIRC4 and in this way caspase 9 becomes free and can activate caspase 3.

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BIRC5

Synonyms: Baculoviral IAP repeat-containing protein 5 (BIRC5), apoptotic inhibitory survivin.

BIRC5 like BIRC3 and 4 has many functions in cell division and inhibition of apoptosis. BIRC5 found in copious amount in human fetal growth, but not in adult tissue, it expressed in large quantity in lung, liver, heart, GIT [34] colon, pancreas, prostate, and breast cancer and transformed cell lines [35], but not in differentiated tissues apart from thymus and placenta. Also highly found in patients with hematologic malignancies [36], lymphomas, acute leukemias, and myelodysplastic syndromes, which leads toward leukemia. Survivin found in copious amount in cancer cells but absent in normal tissues [37]. Tumor resistance to different stimuli increases by caspase-dependent pathway, but in caspase-independent pathway, it can inhibit apoptosis [38, 39]. During mitosis, survivin links with mitotic spindle microtubules, at start of mitosis, and found along with centromeres with caspase-3, and the cyclin-dependent-kinase inhibitor p21Waf1, so that they can form an assembly. Functions are defects in cell division and G2/M phase apoptosis. BIRC5 has double role in cell division regulation and cell death control. Survivin causes apoptosis by preventing microtubules integrity and in centromere regulate cell cycle/cell death by assembly of supramolecular assembly [36] (Figure 6). BIRC5 is the protein that shows antiapoptotic activity along with IAP having only one BIR domain.

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Figure 6. Mode of action of BIRC5/survivin through caspase pathway.

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BIRC6

Synonyms: Baculoviral IAP repeat-containing protein 6 (BIRC6), Baculoviral IAP repeat-containing ubiquitin-conjugating enzyme (BRUCE), Baculoviral IAP repeat-containing 6 (Apollon), FLJ13726, FLJ13786.

BIRC6 is found in high quantity in brain, testis, lymphatic cells, and secretory organs and also in many other tissues. It is found in high quantity in mouse embryos up to E11, then transcript level falls found in the trans Golgi network (TGN) membranes and the endosomal system. It is a member of IAP family. BRUCE is a protein, at amino-terminal having a single survivin-like baculoviral IAP repeat (BIR) domain, and at carboxy-terminal, a ubiquitin-conjugating enzyme domain. Different studies show that BRUCE is a dual regulator of cell proliferation and cell death, as well as BRUCE in mammalian cells is the only essential BIR-containing protein that involves in cell growth and development. BIRC6 is outer membrane protein of the trans Golgi network acts as apoptosis inhibitor by acting as inhibitor of apoptosis protein (IAP). Caspase (3, 6, 7, 8, and 9) can be inhibited by BRUCE (Figure 7). Additionally, it ubiquitylates cHtrA2 (a proapoptotic serine protease) caspase-9, and DIABLO/Smac (a competitor for caspase–IAP interactions) so, act on them for proteasomal degradation. For ubiquitylation reactions, there is no need of ubiquitin E3 ligase which makes BIRC6 a chimeric E2/E3 ubiquitin ligase. BIRC6 is overexpressed in many cell lines of brain and ovarian cancer, overexpression of BIRC6 may correlate with apoptotic reagent resistance. BIRC6 also overexpressed in bone marrow cells of myelodysplastic syndromes. Inhibition of apoptosis is mediated either by caspase binding and or by inhibition. IAP antagonist SMAC as well as caspase 9 ubiquitination so for proteosomal degradation proteins are targeted. Apoptosis is mediated by BIRC6 by ubiquitination and proteasomal degradation [18] (Figure 7).

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Figure 7. Mechanism of action of BIRC6.

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BIRC7

Synonyms: Baculoviral IAP repeat-containing protein 7 (BIRC7), melanoma inhibitor of apoptosis protein (ML-IAP) [43].

BIRC7 functions as apoptotic regulator, shows action by proapoptotic and antiapoptotic activities and helps in apoptosis, cell division, cell cycle arrest. Apoptosis is mediated by caspase 3, 7, 9 and by its E3 ubiquitin–protein ligase activity, anticaspase activity is weak and by ubiquitination DIABLO/SMAC targeting show antiapoptotic activity. By blocking of DIABLO/SMAC disrupt XIAP/BIRC4–caspase interactions show caspase inhibition [41]. TNF or chemical agents such as adriamycin, etoposide, or staurosporine-induced apoptosis can be prevented by BRUCE. Apoptosis suppression is mediated by MAPK8/JNK1, and also by MAPK9/JNK2, activation depends on TAB 1 and NR2C2/TAK1. Caspase 3 is inhibited by and proteolytic activation of procaspase 9 (Figure 8).

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Figure 8. Mechanism of action of BIRC7 via caspase pathway.

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BIRC8

Synonyms: Baculoviral IAP repeat-containing 8 (BIRC8), ILP2, ILP-2, hILP2.

BIRC8 belonging to immunoglobin superfamily acts as a genetic home, having many leukocyte Ig-like receptors, killer cells, several ICAMs, the CEACAM and PSG family and Fc receptors (FcRs). Its function is protection against apoptosis caused by BAX subcellular structure which binds to caspase 9, found in high quantity in cytoplasm. Tissue specificity is in testis [42], cancerous tissue, and in normal tissues. In number of viral and eukaryotic proteins, RING-type zinc-finger motif is present, which is made of cysteine-rich domain that binds with two zinc atoms. ILP2 has role in transformation and progression, which protects cell by Bax-mediated apoptosis. Apollon/livin/ILP2 possesses significant expression in bone marrow cells of myelodysplastic syndromes. After transformation to overt leukemia, apoptosis mediated by Fas and TNF have no protective effect after overexpression of IPL [43].

Conclusion

  1. Top of page
  2. Abstract
  3. Structure of BIR Proteins
  4. Conclusion
  5. Declaration
  6. References
  7. Author Information

Inhibitors of apoptotic proteins (IAPs) can play an important role in inhibiting apoptosis by exerting their negative action on caspases (apoptotic proteins). Deregulation of these inhibitors of apoptotic proteins (IAPs) may push cell toward cancer and neurodegenerative disorders. It is concluded that inhibitors of apoptotic proteins (IAPs) may provide new target for anticancer therapy. Drugs may be developed that are inhibiting these IAPs to induce apoptosis in cancerous cells.

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  1. Top of page
  2. Abstract
  3. Structure of BIR Proteins
  4. Conclusion
  5. Declaration
  6. References
  7. Author Information
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