Diablo homolog

Last updated
DIABLO
Protein DIABLO PDB 1few.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DIABLO , DFNA64, SMAC, Diablo, Diablo homolog, diablo IAP-binding mitochondrial protein
External IDs OMIM: 605219 MGI: 1913843 HomoloGene: 10532 GeneCards: DIABLO
Orthologs
SpeciesHumanMouse
Entrez

56616

66593

Ensembl

ENSG00000184047

ENSMUSG00000029433

UniProt

Q9NR28

Q9JIQ3

RefSeq (mRNA)

NM_023232

RefSeq (protein)

NP_075721

Location (UCSC) Chr 12: 122.21 – 122.23 Mb Chr 5: 123.65 – 123.66 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO (direct IAP binding protein with low pI) gene on chromosome 12. [5] [6] [7] DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. [7] [8] Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments. [7] [9]

Structure

Protein

This gene encodes a 130 Å-long, arch-shaped homodimer protein. The full-length protein product spans 239 residues, 55 of which comprise the mitochondrial-targeting sequence (MTS) at its N-terminal. However, once the full-length protein is imported into the mitochondria, this sequence is excised to produce the 184-residue mature protein. [9] [10] [11] This cleavage also exposes four residues at the N-terminal, Ala-Val-Pro-Ile (AVPI), which is the core of the IAP binding domain and crucial for inhibiting XIAP. [9] [10] [11] Specifically, the tetrapeptide sequence binds the BIR3 domain of XIAP to form a stable complex between SMAC and XIAP. [9] [10] [11] The homodimer structure also facilitates SMAC-XIAP binding via the BIR2 domain, though it does not form until the protein is released into the cytoplasm as a result of outer mitochondrial membrane permeabilization. [11] Thus, monomeric SMAC mutants can still bind the BIR3 domain but not the BIR2 domain, which compromises the protein’s inhibitory function. [10] Meanwhile, mutations within the AVPI sequence lead to loss of function, though SMAC may still be able to perform IAP binding-independent functions, such as inducing the ubiquitinylation of XIAP. [10] [12]

Gene

Several alternatively spliced transcript variants that encode distinct isoforms have been described for this gene, but the validity of some transcripts, and their predicted ORFs, has not been determined conclusively. [7] [10] Two known isoforms both lack the MTS and the IAP binding domain, suggesting differential subcellular localization and function. [12]

Function

SMAC is a mitochondrial protein that promotes cytochrome c- and TNF receptor-dependent activation of apoptosis by inhibiting the effect of IAP – a group of proteins that negatively regulate apoptosis, or programmed cell death. [8] [13] SMAC is normally a mitochondrial protein localized to the mitochondrial intermembrane space, but it enters the cytosol when cells undergo apoptosis. [7] [10] [12] [14] Through the intrinsic pathway of apoptosis, BCL-2 proteins like BAK and BAX form a pore in the outer mitochondrial membrane, leading to mitochondrial membrane permeabilization and the release of both cytochrome c and SMAC. [9] [10] While cytochrome c directly activates APAF1 and caspase 9, SMAC binds IAPs, such as XIAP and cIAP proteins, to inhibit their caspase-binding activity and allow for caspase activation of apoptosis. [7] [9] [10] [12] [14] SMAC is ubiquitously expressed in many cell types, implicating it in various biological processes involving apoptosis. [15] Currently, nonapoptotic functions for SMAC remain unclear. [11]

Clinical significance

SMAC is involved in cancer, and its overexpression is linked to increased sensitivity in tumor cells to apoptosis. [7] [13] So far, SMAC overexpression has been observed to oppose cancer progression in head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin lymphoma, breast cancer, glioblastoma, thyroid cancer, renal cell carcinoma, testicular germ cell tumors, colorectal cancer, lung cancer, bladder cancer, endometrioid endometrial cancer, and other sarcomas. [13] [15] [16] However, the exact relationship between SMAC and leukemia and hematological diseases remains controversial. SMAC mimetics monotherapy displays improved cytotoxic effects on leukemic cell lines compared to combined therapy with other drugs, which is commonly more effective in other types of cancers. [17]

Following experimental elucidation of SMAC structure, small-molecule SMAC mimetics have been developed to mimic the tetrapeptide AVPI in the IAP binding domain of SMAC, which is responsible for binding the BIR3 domains in IAPs like XIAP, cIAP1, and cIAP2 to induce apoptosis, and sometimes, necroptosis. [9] [16] Several of the numerous SMAC mimetics designed within the last decade or so are now undergoing clinical trials, including SM-406 by Bai and colleagues and two mimetics by Genentech. These mimetics are also designed to target tumor cells directly through interacting with inflammatory proteins, such as IL-1β, which are commonly produced by solid tumor lesions. [9] Notably, preclinical studies indicate that the use of SMAC mimetics in conjunction with chemotherapy, death receptor ligands and agonists, as well as small molecule targeted drugs enhance the sensitivity of tumor cells to these treatments. [9] [13] [16] In addition to improving the success of tumor elimination, this increased sensitivity can permit smaller doses, thus minimizing side effects while maintaining efficacy. [16] Nonetheless, there still exists the potential for side effects, such as elevated levels of cytokines and chemokines in normal tissues, depending on the cellular environment. [9]

In addition to cancers, mutations in DIABLO is associated with young-adult onset of nonsyndromic deafness-64. [7]

Interactions

Diablo homolog has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Apoptosome</span>

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

<span class="mw-page-title-main">Fas receptor</span> Protein found in humans

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Survivin</span> Mammalian protein

Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene.

<span class="mw-page-title-main">Caspase-9</span> Protein-coding gene in the species Homo sapiens

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

<span class="mw-page-title-main">Caspase 8</span> Protein-coding gene in the species Homo sapiens

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

<span class="mw-page-title-main">XIAP</span> Protein-coding gene in the species Homo sapiens

X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a protein that stops apoptotic cell death. In humans, this protein (XIAP) is produced by a gene named XIAP gene located on the X chromosome.

<span class="mw-page-title-main">Caspase 3</span> Protein-coding gene in the species Homo sapiens

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

Nerve tissue is a biological molecule related to the function and maintenance of normal nervous tissue. An example would include, for example, the generation of myelin which insulates and protects nerves. These are typically calcium-binding proteins.

<span class="mw-page-title-main">Caspase 7</span> Protein-coding gene in the species Homo sapiens

Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Baculoviral IAP repeat-containing protein 3</span> Protein-coding gene in the species Homo sapiens

Baculoviral IAP repeat-containing protein3 is a protein that in humans is encoded by the BIRC3 gene.

<span class="mw-page-title-main">Baculoviral IAP repeat-containing protein 2</span> Protein-coding gene in the species Homo sapiens

Baculoviral IAP repeat-containing protein 2 is a protein that in humans is encoded by the BIRC2 gene.

<span class="mw-page-title-main">Caspase 10</span> Protein-coding gene in the species Homo sapiens

Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.

<span class="mw-page-title-main">APAF1</span> Mammalian protein found in Homo sapiens

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.

<span class="mw-page-title-main">HtrA serine peptidase 2</span> Enzyme found in humans

Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene. This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.

<span class="mw-page-title-main">BIRC7</span> Protein-coding gene in the species Homo sapiens

Baculoviral IAP repeat-containing protein 7 is a protein that in humans is encoded by the BIRC7 gene.

<span class="mw-page-title-main">XAF1</span> Protein-coding gene in the species Homo sapiens

XIAP-associated factor 1 is a protein that in humans is encoded by the XAF1 gene.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000184047 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029433 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ McNeish IA, Bell S, McKay T, Tenev T, Marani M, Lemoine NR (June 2003). "Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway". Experimental Cell Research. 286 (2): 186–98. doi:10.1016/S0014-4827(03)00073-9. PMID   12749848.
  6. ↑ Yu J, Wang P, Ming L, Wood MA, Zhang L (June 2007). "SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events". Oncogene. 26 (29): 4189–98. doi:10.1038/sj.onc.1210196. PMID   17237824. S2CID   25230886.
  7. 1 2 3 4 5 6 7 8 "Entrez Gene: DIABLO diablo homolog (Drosophila)".
  8. 1 2 Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ, Dixit VM (April 2002). "SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP)". The Journal of Biological Chemistry. 277 (14): 12275–9. doi: 10.1074/jbc.M112045200 . PMID   11801603.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 13 Bai L, Smith DC, Wang S (October 2014). "Small-molecule SMAC mimetics as new cancer therapeutics". Pharmacology & Therapeutics. 144 (1): 82–95. doi:10.1016/j.pharmthera.2014.05.007. PMC   4247261 . PMID   24841289.
  10. 1 2 3 4 5 6 7 8 9 10 11 12 13 Shi Y (May 2001). "A structural view of mitochondria-mediated apoptosis". Nature Structural Biology. 8 (5): 394–401. doi:10.1038/87548. PMID   11323712. S2CID   19501646.
  11. 1 2 3 4 5 Galluzzi L, Joza N, Tasdemir E, Maiuri MC, Hengartner M, Abrams JM, Tavernarakis N, Penninger J, Madeo F, Kroemer G (July 2008). "No death without life: vital functions of apoptotic effectors". Cell Death and Differentiation. 15 (7): 1113–23. doi:10.1038/cdd.2008.28. PMC   2917777 . PMID   18309324.
  12. 1 2 3 4 Martinez-Ruiz GU, Victoria-Acosta G, Vazquez-Santillan KI, Jimenez-Hernandez L, Muñoz-Galindo L, Ceballos-Cancino G, Maldonado V, Melendez-Zajgla J (2014). "Ectopic expression of new alternative splice variant of Smac/DIABLO increases mammospheres formation". International Journal of Clinical and Experimental Pathology. 7 (9): 5515–26. PMC   4203164 . PMID   25337193.
  13. 1 2 3 4 Zeng H, Zhang S, Yang KY, Wang T, Hu JL, Huang LL, Wu G (December 2010). "Knockdown of second mitochondria-derived activator of caspase expression by RNAi enhances growth and cisplatin resistance of human lung cancer cells". Cancer Biotherapy & Radiopharmaceuticals. 25 (6): 705–12. doi:10.1089/cbr.2010.0786. PMID   21204765.
  14. 1 2 Anguiano-Hernandez YM, Chartier A, Huerta S (July 2007). "Smac/DIABLO and colon cancer". Anti-Cancer Agents in Medicinal Chemistry. 7 (4): 467–73. doi:10.2174/187152007781058631. PMID   17630921.
  15. 1 2 Dobrzycka B, Terlikowski SJ, Bernaczyk PS, Garbowicz M, Niklinski J, Chyczewski L, Kulikowski M (December 2010). "Prognostic significance of smac/DIABLO in endometrioid endometrial cancer". Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society. 48 (4): 678–81. doi: 10.2478/v10042-010-0091-2 . PMID   21478115.
  16. 1 2 3 4 Sun Q, Zheng X, Zhang L, Yu J (April 2011). "Smac modulates chemosensitivity in head and neck cancer cells through the mitochondrial apoptotic pathway". Clinical Cancer Research. 17 (8): 2361–72. doi:10.1158/1078-0432.CCR-10-2262. PMC   3079009 . PMID   21242120.
  17. ↑ Scavullo C, Servida F, Lecis D, Onida F, Drago C, Ferrante L, Seneci P, Barcellini W, Lionetti M, Todoerti K, Neri A, Delia D, Deliliers GL (July 2013). "Single-agent Smac-mimetic compounds induce apoptosis in B chronic lymphocytic leukaemia (B-CLL)". Leukemia Research. 37 (7): 809–15. doi:10.1016/j.leukres.2013.03.016. PMID   23618690.
  18. ↑ Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z, Cheong N, Nejmeh J, Fernandes-Alnemri T, Hoshino S, Alnemri ES (October 2003). "The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein". The Journal of Biological Chemistry. 278 (40): 38699–706. doi: 10.1074/jbc.M303179200 . PMID   12865429.
  19. 1 2 Song Z, Yao X, Wu M (June 2003). "Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis". The Journal of Biological Chemistry. 278 (25): 23130–40. doi: 10.1074/jbc.M300957200 . PMID   12660240.
  20. ↑ Kuai J, Nickbarg E, Wooters J, Qiu Y, Wang J, Lin LL (April 2003). "Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis". The Journal of Biological Chemistry. 278 (16): 14363–9. doi: 10.1074/jbc.M208672200 . PMID   12571250.
  21. ↑ Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (July 2000). "Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins". Cell. 102 (1): 43–53. doi: 10.1016/s0092-8674(00)00009-x . PMID   10929712. S2CID   3192775.
  22. ↑ Hunter AM, Kottachchi D, Lewis J, Duckett CS, Korneluk RG, Liston P (February 2003). "A novel ubiquitin fusion system bypasses the mitochondria and generates biologically active Smac/DIABLO". The Journal of Biological Chemistry. 278 (9): 7494–9. doi: 10.1074/jbc.C200695200 . PMID   12511567.
  23. ↑ Davoodi J, Lin L, Kelly J, Liston P, MacKenzie AE (September 2004). "Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9". The Journal of Biological Chemistry. 279 (39): 40622–8. doi: 10.1074/jbc.M405963200 . PMID   15280366.
  24. ↑ Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (Jan 2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". The Journal of Biological Chemistry. 277 (1): 445–54. doi: 10.1074/jbc.M109891200 . PMID   11604410.

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