Advertisement

Database and Bioinformatic Analysis of BCL-2 Family Proteins and BH3-Only Proteins

  • Abdel Aouacheria
  • Vincent Navratil
  • Christophe Combet
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1877)

Abstract

BCL-2 proteins correspond to a structurally, functionally, and phylogenetically heterogeneous group of regulators that play crucial roles in the life and death of animal cells. Some of these regulators also represent therapeutic targets in human diseases including cancer. In the omics era, there is great need for easy data retrieval and fast analysis of the molecular players involved in cell death. In this chapter, we present generic and specific computational resources (such as the reference database BCL2DB) as well as bioinformatics tools that can be used to investigate BCL-2 homologs and BH3-only proteins.

Key words

Databases Bioinformatics Omics Structure–function relationships Protein domains Protein motifs BCL-2 BH3 Apoptosis Cell death 

Notes

Acknowledgment

This work was supported by CNRS and Montpellier University. We also acknowledge financial support from the Fondation ARC (AA) and Ligue Contre le Cancer ComitÕ du Gard (AA).

References

  1. 1.
    Bhola PD, Letai A (2016) Mitochondria-judges and executioners of cell death sentences. Mol Cell 61(5):695–704.  https://doi.org/10.1016/j.molcel.2016.02.019CrossRefGoogle Scholar
  2. 2.
    Moldoveanu T, Follis AV, Kriwacki RW, Green DR (2014) Many players in BCL-2 family affairs. Trends Biochem Sci 39(3):101–111.  https://doi.org/10.1016/j.tibs.2013.12.006CrossRefGoogle Scholar
  3. 3.
    Delbridge AR, Strasser A (2015) The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ 22(7):1071–1080.  https://doi.org/10.1038/cdd.2015.50CrossRefGoogle Scholar
  4. 4.
    Garner TP, Lopez A, Reyna DE, Spitz AZ, Gavathiotis E (2017) Progress in targeting the BCL-2 family of proteins. Curr Opin Chem Biol 39:133–142.  https://doi.org/10.1016/j.cbpa.2017.06.014CrossRefGoogle Scholar
  5. 5.
    Schenk RL, Strasser A, Dewson G (2017) BCL-2: long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun 482(3):459–469.  https://doi.org/10.1016/j.bbrc.2016.10.100CrossRefGoogle Scholar
  6. 6.
    Aouacheria A, Combet C, Tompa P, Hardwick JM (2015) Redefining the BH3 death domain as a ‘Short linear motif’. Trends Biochem Sci 40(12):736–748.  https://doi.org/10.1016/j.tibs.2015.09.007CrossRefGoogle Scholar
  7. 7.
    Aouacheria A, Rech de Laval V, Combet C, Hardwick JM (2013) Evolution of Bcl-2 homology motifs: homology versus homoplasy. Trends Cell Biol 23(3):103–111.  https://doi.org/10.1016/j.tcb.2012.10.010CrossRefGoogle Scholar
  8. 8.
    Zheng JH, Viacava Follis A, Kriwacki RW, Moldoveanu T (2016) Discoveries and controversies in BCL-2 protein-mediated apoptosis. FEBS J 283(14):2690–2700.  https://doi.org/10.1111/febs.13527CrossRefGoogle Scholar
  9. 9.
    Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15(1):49–63.  https://doi.org/10.1038/nrm3722CrossRefGoogle Scholar
  10. 10.
    Delbridge AR, Grabow S, Strasser A, Vaux DL (2016) Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 16(2):99–109.  https://doi.org/10.1038/nrc.2015.17CrossRefGoogle Scholar
  11. 11.
    Tait SW, Green DR (2013) Mitochondrial regulation of cell death. Cold Spring Harb Perspect Biol 5(9).  https://doi.org/10.1101/cshperspect.a008706CrossRefGoogle Scholar
  12. 12.
    Uren RT, Iyer S, Kluck RM (2017) Pore formation by dimeric Bak and Bax: an unusual pore? Philos Trans R Soc Lond B Biol Sci 372(1726).  https://doi.org/10.1098/rstb.2016.0218CrossRefGoogle Scholar
  13. 13.
    Aouacheria A (2014) The BCL-2 database, Act 2: moving beyond dualism to diversity and pleiotropy. Cell Death Dis 5:e981.  https://doi.org/10.1038/cddis.2013.511CrossRefGoogle Scholar
  14. 14.
    Bae J, Leo CP, Hsu SY, Hsueh AJ (2000) MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem 275(33):25255–25261.  https://doi.org/10.1074/jbc.M909826199CrossRefGoogle Scholar
  15. 15.
    Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB (1993) Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74(4):597–608CrossRefGoogle Scholar
  16. 16.
    Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278(5345):1966–1968CrossRefGoogle Scholar
  17. 17.
    Kucharczak JF, Simmons MJ, Duckett CS, Gelinas C (2005) Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor. Cell Death Differ 12(9):1225–1239.  https://doi.org/10.1038/sj.cdd.4401684CrossRefGoogle Scholar
  18. 18.
    Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ (1995) Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature 374(6524):736–739.  https://doi.org/10.1038/374736a0CrossRefGoogle Scholar
  19. 19.
    Aouacheria A, Arnaud E, Venet S, Lalle P, Gouy M, Rigal D, Gillet G (2001) Nrh, a human homologue of Nr-13 associates with Bcl-Xs and is an inhibitor of apoptosis. Oncogene 20(41):5846–5855.  https://doi.org/10.1038/sj.onc.1204740CrossRefGoogle Scholar
  20. 20.
    Inohara N, Gourley TS, Carrio R, Muniz M, Merino J, Garcia I, Koseki T, Hu Y, Chen S, Nunez G (1998) Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. J Biol Chem 273(49):32479–32486CrossRefGoogle Scholar
  21. 21.
    Jensen SA, Calvert AE, Volpert G, Kouri FM, Hurley LA, Luciano JP, Wu Y, Chalastanis A, Futerman AH, Stegh AH (2014) Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc Natl Acad Sci U S A 111(15):5682–5687.  https://doi.org/10.1073/pnas.1316700111CrossRefGoogle Scholar
  22. 22.
    Kataoka T, Holler N, Micheau O, Martinon F, Tinel A, Hofmann K, Tschopp J (2001) Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension. J Biol Chem 276(22):19548–19554.  https://doi.org/10.1074/jbc.M010520200CrossRefGoogle Scholar
  23. 23.
    Ke N, Godzik A, Reed JC (2001) Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J Biol Chem 276(16):12481–12484.  https://doi.org/10.1074/jbc.C000871200CrossRefGoogle Scholar
  24. 24.
    Lee R, Chen J, Matthews CP, McDougall JK, Neiman PE (2001) Characterization of NR13-related human cell death regulator, boo/diva, in normal and cancer tissues. Biochim Biophys Acta 1520(3):187–194CrossRefGoogle Scholar
  25. 25.
    Song Q, Kuang Y, Dixit VM, Vincenz C (1999) Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J 18(1):167–178.  https://doi.org/10.1093/emboj/18.1.167CrossRefGoogle Scholar
  26. 26.
    Zhang H, Holzgreve W, De Geyter C (2001) Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. Hum Mol Genet 10(21):2329–2339CrossRefGoogle Scholar
  27. 27.
    Aouacheria A, Baghdiguian S, Lamb HM, Huska JD, Pineda FJ, Hardwick JM (2017) Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins. Neurochem Int.  https://doi.org/10.1016/j.neuint.2017.04.009CrossRefGoogle Scholar
  28. 28.
    Gross A (2006) BID as a double agent in cell life and death. Cell Cycle 5(6):582–584CrossRefGoogle Scholar
  29. 29.
    Hardwick JM, Soane L (2013) Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol 5(2).  https://doi.org/10.1101/cshperspect.a008722CrossRefGoogle Scholar
  30. 30.
    Kvansakul M, Hinds MG (2015) The Bcl-2 family: structures, interactions and targets for drug discovery. Apoptosis 20(2):136–150.  https://doi.org/10.1007/s10495-014-1051-7CrossRefGoogle Scholar
  31. 31.
    Petros AM, Olejniczak ET, Fesik SW (2004) Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644(2–3):83–94.  https://doi.org/10.1016/j.bbamcr.2003.08.012CrossRefGoogle Scholar
  32. 32.
    Aouacheria A, Le Goff E, Godefroy N, Baghdiguian S (2016) Evolution of the BCL-2-regulated apoptotic pathway. In: Pontarotti P (ed) Evolutionary biology. Springer, Switzerland, pp 137–156.  https://doi.org/10.1007/978-3-319-41324-2_9CrossRefGoogle Scholar
  33. 33.
    Graham SC, Bahar MW, Cooray S, Chen RA, Whalen DM, Abrescia NG, Alderton D, Owens RJ, Stuart DI, Smith GL, Grimes JM (2008) Vaccinia virus proteins A52 and B14 share a Bcl-2-like fold but have evolved to inhibit NF-kappaB rather than apoptosis. PLoS Pathog 4(8):e1000128.  https://doi.org/10.1371/journal.ppat.1000128CrossRefGoogle Scholar
  34. 34.
    Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SL, Fesik SW (1996) X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381(6580):335–341.  https://doi.org/10.1038/381335a0CrossRefGoogle Scholar
  35. 35.
    Neidel S, Maluquer de Motes C, Mansur DS, Strnadova P, Smith GL, Graham SC (2015) Vaccinia virus protein A49 is an unexpected member of the B-cell lymphoma (Bcl)-2 protein family. J Biol Chem 290(10):5991–6002.  https://doi.org/10.1074/jbc.M114.624650CrossRefGoogle Scholar
  36. 36.
    Kvansakul M, Hinds MG (2014) The structural biology of BH3-only proteins. Methods Enzymol 544:49–74.  https://doi.org/10.1016/B978-0-12-417158-9.00003-0CrossRefGoogle Scholar
  37. 37.
    Aouacheria A, Brunet F, Gouy M (2005) Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-only, and BNip families of apoptotic regulators. Mol Biol Evol 22(12):2395–2416.  https://doi.org/10.1093/molbev/msi234CrossRefGoogle Scholar
  38. 38.
    Bender CE, Fitzgerald P, Tait SW, Llambi F, McStay GP, Tupper DO, Pellettieri J, Sanchez Alvarado A, Salvesen GS, Green DR (2012) Mitochondrial pathway of apoptosis is ancestral in metazoans. Proc Natl Acad Sci U S A 109(13):4904–4909.  https://doi.org/10.1073/pnas.1120680109CrossRefGoogle Scholar
  39. 39.
    Lee EF, Clarke OB, Evangelista M, Feng Z, Speed TP, Tchoubrieva EB, Strasser A, Kalinna BH, Colman PM, Fairlie WD (2011) Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes. Proc Natl Acad Sci U S A 108(17):6999–7003.  https://doi.org/10.1073/pnas.1100652108CrossRefGoogle Scholar
  40. 40.
    Prudent J, Popgeorgiev N, Bonneau B, Thibaut J, Gadet R, Lopez J, Gonzalo P, Rimokh R, Manon S, Houart C, Herbomel P, Aouacheria A, Gillet G (2013) Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish. Nat Commun 4:2330.  https://doi.org/10.1038/ncomms3330CrossRefGoogle Scholar
  41. 41.
    Aouacheria A, Banyai M, Rigal D, Schmidt CJ, Gillet G (2003) Characterization of vnr-13, the first alphaherpesvirus gene of the bcl-2 family. Virology 316(2):256–266CrossRefGoogle Scholar
  42. 42.
    Rech de Laval V, Deleage G, Aouacheria A, Combet C (2014) BCL2DB: database of BCL-2 family members and BH3-only proteins. Database 2014.  https://doi.org/10.1093/database/bau013CrossRefGoogle Scholar
  43. 43.
    Galperin MY, Fernandez-Suarez XM, Rigden DJ (2017) The 24th annual nucleic acids research database issue: a look back and upcoming changes. Nucleic Acids Res 45(9):5627.  https://doi.org/10.1093/nar/gkx021CrossRefGoogle Scholar
  44. 44.
    Alavian KN, Li H, Collis L, Bonanni L, Zeng L, Sacchetti S, Lazrove E, Nabili P, Flaherty B, Graham M, Chen Y, Messerli SM, Mariggio MA, Rahner C, McNay E, Shore GC, Smith PJ, Hardwick JM, Jonas EA (2011) Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat Cell Biol 13(10):1224–1233.  https://doi.org/10.1038/ncb2330CrossRefGoogle Scholar
  45. 45.
    Chen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM, Cheng WC, Qi B, Li H, Alavian KN, Dayhoff-Brannigan M, Zou S, Pineda FJ, O'Rourke B, Ko YH, Pedersen PL, Kaczmarek LK, Jonas EA, Hardwick JM (2011) Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 195(2):263–276.  https://doi.org/10.1083/jcb.201108059CrossRefGoogle Scholar
  46. 46.
    Rung J, Brazma A (2013) Reuse of public genome-wide gene expression data. Nat Rev Genet 14(2):89–99.  https://doi.org/10.1038/nrg3394CrossRefGoogle Scholar
  47. 47.
    Arntzen MO, Thiede B (2012) ApoptoProteomics, an integrated database for analysis of proteomics data obtained from apoptotic cells. Mol Cell Proteomics 11(2).  https://doi.org/10.1074/mcp.M111.010447CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Abdel Aouacheria
    • 1
  • Vincent Navratil
    • 2
  • Christophe Combet
    • 3
  1. 1.ISEM, Institut des Sciences de l’Evolution de MontpellierUniversité de Montpellier, UMR 5554, CNRS, IRD, EPHEMontpellierFrance
  2. 2.PRABI, Rhône Alpes Bioinformatics Center, UCBL, Lyon1Université de LyonLyonFrance
  3. 3.Centre de Recherche en Cancérologie de LyonUMR Inserm U1052, CNRS 5286, Université Claude Bernard Lyon 1, Centre Léon BérardLyonFrance

Personalised recommendations