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Death by Caspase Dimerization

  • Sarah H. MacKenzie
  • A. Clay ClarkEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 747)

Abstract

Controlled cell death, or apoptosis, occurs in response to many different environmental stimuli. The apoptotic cascade that occurs within the cell in response to these cues leads to morphological and biochemical changes that trigger the dismantling and packaging of the cell. Caspases are a family of cysteine-dependent aspartate-directed proteases that play an integral role in the cascade that leads to apoptosis. Caspases are grouped as either initiators or effectors of apoptosis, depending on where they enter the cell death process. Prior to activation, initiator caspases are present as monomers that must dimerize for full activation whereas effector caspases are present as dimeric zymogens that must be processed for full activation. The stability of the dimer may be due predominately to the interactions in the dimer interface as each caspase has unique properties in this region that lend to its specific mode of activation. Moreover, dimerization is responsible for active site formation because both monomers contribute residues that enable the formation of a fully functional active site. Overall, dimerization plays a key role in the ability of caspases to form fully functional proteases.

Keywords

Adaptor Molecule Central Cavity Dime Interface Protein Dimerization Allosteric Site 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Jacobson MD, Weill M, Raff MC. Programmed cell death in animal development. Cell 1997; 88:347–354.PubMedCrossRefGoogle Scholar
  2. 2.
    Fadeel B, Orrenius S. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Internal Med 2005; 258:479–517.PubMedCrossRefGoogle Scholar
  3. 3.
    Kabore AF, Johnston JB, Gibson SB. Changes in the apoptotic and survival signaling in cancer cells and their potential therapeutic implications. Current Cancer Drug Targets 2004; 4:147–163.PubMedCrossRefGoogle Scholar
  4. 4.
    Fulda S, Debatin K-M. Targeting apoptosis pathways in cancer therapy. Current Cancer Drug Targets 2004; 4:569–576.PubMedCrossRefGoogle Scholar
  5. 5.
    Meng XW, Lee S-H, Kaufmann SH. Apoptosis in the treatment of cancer: a promise kept? Curr Op Cell Biol 2006; 18:668–676.PubMedCrossRefGoogle Scholar
  6. 6.
    Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates and functions during apoptosis. Ann Rev Biochem 1999; 68:383–424.PubMedCrossRefGoogle Scholar
  7. 7.
    Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Intern Rev Cytol 1980; 68:251–306.CrossRefGoogle Scholar
  8. 8.
    Kaufmann SH. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 1989; 49:5870–5878.PubMedGoogle Scholar
  9. 9.
    Canman CE, Tange H-Y, Normolle DP et al. Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine: implications for mechanisms of resistance and cytotoxicity. Proc Natl Acad Sci 1992; 89:10474–10478.PubMedCrossRefGoogle Scholar
  10. 10.
    Jin Z, El-Deiry W. Overview of cell death signaling pathways. Cancer Biology and Therapy 2005; 4:139–163.PubMedCrossRefGoogle Scholar
  11. 11.
    Enari M, Sakahira H, Yokoyama H et al. A caspase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD. Nature. 1998; 391:43–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Fuentes-Prior P, Salvesen GS. The protein structures that shape caspase activity, specificity activation and inhibition. Biochem J 2004; 384:201–232.PubMedCrossRefGoogle Scholar
  13. 13.
    Thornberry NA, Bull HG, Calaycay JR et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 1992; 356:768–774.PubMedCrossRefGoogle Scholar
  14. 14.
    Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004; 117:561–574.PubMedCrossRefGoogle Scholar
  15. 15.
    Ahn E-Y, Pan G, Vickers SM et al. IFN-γ upregulates apoptosis-related molecules and enhances FAS-mediated apoptosis in human cholangiocarcinoma. Intern J Cancer 2002; 100:445–451.CrossRefGoogle Scholar
  16. 16.
    Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Op Cell Biol 2003; 15:725–731.PubMedCrossRefGoogle Scholar
  17. 17.
    Boatright KM, Renatus M, Scott FL et al. A unified model for apical caspase activation. Mol Cell 2003; 11:529–541.PubMedCrossRefGoogle Scholar
  18. 18.
    Leung BP, Culshaw S, Gracie JA et al. A role for IL-18 in neutrophil activation. J Immunol 2001; 167:2879–2886.PubMedGoogle Scholar
  19. 19.
    Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell 2002; 10:417–426.PubMedCrossRefGoogle Scholar
  20. 20.
    Thornberry NA, Rano TA, Peterson EP et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. J Biol Chem 1997; 272:17907–17911.PubMedCrossRefGoogle Scholar
  21. 21.
    Schweizer A, Briand C, Grutter MG. Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway. J Biol Chem 2003; 278:42441–42447.PubMedCrossRefGoogle Scholar
  22. 22.
    Hofmann K, Bucher P, Tschopp J. The CARD domain: a new apoptotic signalling motif. Trends Biochem Sci 1997; 22:155–156.PubMedCrossRefGoogle Scholar
  23. 23.
    Thome M, Hofmann K, Burns K et al. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr Biol 1998; 8:885–888.PubMedCrossRefGoogle Scholar
  24. 24.
    Weber CH, Vincenz C. The death domain superfamily: a tale of two interfaces? Trends Biochem Sci 2001; 26:475–481.PubMedCrossRefGoogle Scholar
  25. 25.
    Feeney B, Clark AC. Reassembly of active caspase-3 is facilitated by the propeptide. J Biol Chem 2005; 280:39772–39785.PubMedCrossRefGoogle Scholar
  26. 26.
    Denault J-B, Salvesen GS. Human caspase-7 activity and regulation by its N-terminal peptide. J Biol Chem 2003; 278:34042–34050.PubMedCrossRefGoogle Scholar
  27. 27.
    Meergans T, Hildebrandt A-K, Horak D et al. The short prodomain influences caspase-3 activation in HeLa cells. Biochem J 2000; 349:135–140.PubMedCrossRefGoogle Scholar
  28. 28.
    Cowling V, Downward J. Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death and Differentiation 2002; 9:1046–1056.PubMedCrossRefGoogle Scholar
  29. 29.
    Muzio M, Stockwell BR, Stennicke H et al. An induced proximity model for capase-8 activation. J Biol Chem 1998; 273:2926–2930.PubMedCrossRefGoogle Scholar
  30. 30.
    Pop C, Timmer J, Sperandio S et al. The apoptosome activates caspase-9 by dimerization. Mol Cell 2006; 22:269–275.PubMedCrossRefGoogle Scholar
  31. 31.
    Boatright KM, Renatus M, Scott FL et al. A unified model for apical caspase activation. Mol Cell 2003; 11:529–541.PubMedCrossRefGoogle Scholar
  32. 32.
    Renatus M, Stennicke HR, Scott FL et al. Dimer formation drives the activation of the cell death protease caspase 9. Proc Natl Acad Sci 2001; 98:14250–14255.PubMedCrossRefGoogle Scholar
  33. 33.
    Li H, Bergeron L, Cryns V et al. Activation of caspase-2 in apoptosis. J Biol Chem 1997; 272:21010–21017.PubMedCrossRefGoogle Scholar
  34. 34.
    Baliga BC, Read SH, Kumar S. The biochemical mechanism of caspase-2 activation. Cell Death and Differentiation. 2004; 11:1234–1241.PubMedCrossRefGoogle Scholar
  35. 35.
    Launay S, Hermine O, Fontenay M et al. Vital functions for lethal caspases. Oncogene 2005; 24:5137–5148.PubMedCrossRefGoogle Scholar
  36. 36.
    Bose K, Clark AC. Dimeric procaspase-3 unfolds via a four-state equilibrium process. Biochemistry 2001; 40:14236–14242.PubMedCrossRefGoogle Scholar
  37. 37.
    Bose K, Clark AC. pH effects on the stability and dimerization of procaspase-3. Protein Sci 2005; 14:24–36.PubMedCrossRefGoogle Scholar
  38. 38.
    Matsuyama S, Llopis J, Deveraux QL et al. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol 2000; 2:318–325.PubMedCrossRefGoogle Scholar
  39. 39.
    Bose K, Pop C, Feeney B et al. An uncleavable procaspase-3 mutant has a lower catalytic efficiency but an active site similar to that of mature caspase-3. Biochemistry 2003; 42:12298–12310.PubMedCrossRefGoogle Scholar
  40. 40.
    Mittl PRE, DiMarco S, Krebs JF et al. Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-asp-val-ala-asp fluoromethyl ketone. J Biol Chem 1997; 272:6539–6547.PubMedCrossRefGoogle Scholar
  41. 41.
    Ganesan R, Mittl PRE, Jelakovic S et al. Extended substrate recognition in caspase-3 revealed by high resolution X-ray structure analysis. J Mol Biol 2006; 359:1378–1388.PubMedCrossRefGoogle Scholar
  42. 42.
    Richardson JS, Richardson DC. Natural β—sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci 2002; 99:2754–2759.PubMedCrossRefGoogle Scholar
  43. 43.
    Scheer JM, Romanowski MJ, Wells JA. A common allosteric site and mechanism in caspases. Proc Natl Acad Sci 2006; 103:7595–7600.PubMedCrossRefGoogle Scholar
  44. 44.
    Blanchard H, Kodandapani L, Mittl PRE et al. The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis. Structure 1999; 7:1125–1133.PubMedCrossRefGoogle Scholar
  45. 45.
    Chai J, Wu Q, Shiozaki E et al. Crystal structure of a procaspase-7 zymogen: Mechanisms of activation and substrate binding. Cell 2001; 107:399–407.PubMedCrossRefGoogle Scholar
  46. 46.
    Riedl SJ, Fuentes-Prior P, Renatus M et al. Structural basis for the activation of human procaspase-7. Proc Natl Acad Sci 2001; 98:14790–14795.PubMedCrossRefGoogle Scholar
  47. 47.
    Wilson KP, Black J-AF, Thomson JA et al. Structure and mechanism of interleukin-1β converting enzyme. Nature 1994; 370:270–275.PubMedCrossRefGoogle Scholar
  48. 48.
    Romanowski MJ, Scheer JM, O’Brien T et al. Crystal structures of ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding. Structure 2004; 12:1361–1371.PubMedCrossRefGoogle Scholar
  49. 49.
    Hardy JA, Lam J, Nguyen JT et al. Discovery of an allosteric site in the caspases. Proc Natl Acad Sci 2004; 101:12461–12466.PubMedCrossRefGoogle Scholar
  50. 50.
    Walters J, Pop C, Scott FL et al. A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis. Biophys J 2009; 424:335–345.Google Scholar
  51. 51.
    Schipper JL, MacKenzie SH, Sharma A, Clark AC. A bifunctional allosteric site in the dimer interface of procaspase-3. Biophys Chem 2011; 159:100–109.PubMedCrossRefGoogle Scholar
  52. 52.
    Wolan DW, Zorn JA, Gray DC, Wells JA. Small molecule activators of a proenzyme. Science 2009; 326:853–858PubMedCrossRefGoogle Scholar
  53. 53.
    Peterson QP, Goode DR, West DC, Ramsey KN, Lee JJ, Hergenrother PJ. PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition. J Mol Biol 2009; 388:144–158.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Department of Molecular and Structural BiochemistryNorth Carolina State UniversityRaleighUSA

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