Portal de Periódicos da CAPES

Suicidal Tendencies: Apoptotic Cell Death by Caspase Family Proteinases

1999; Elsevier BV; Volume: 274; Issue: 29 Linguagem: Inglês

10.1074/jbc.274.29.20049

1083-351X

Beni B. Wolf, Douglas R. Green,

Trace Elements in Health

Certain proteases are not merely degradative enzymes but are highly regulated signaling molecules that control critical biological processes via specific limited proteolysis. Caspase proteinases and their central role in apoptotic cell death provide a prime example of this concept. These cysteine proteinases exist as latent zymogens; however, once activated by apoptotic signals, they systematically dismantle and package the cell by cleaving key cellular proteins solely after aspartate residues. Here we review caspase proteinases with an emphasis on their structure, activation, and critical role in the apoptotic mechanism. In 1993, researchers discovered that the Caenorhabditis elegans cell death gene, ced-3, had remarkable sequence similarity to interleukin-1β-converting enzyme (caspase-1), a mammalian proteinase responsible for proteolytic maturation of pro-interleukin-1β (1Yuan J. Shaham S. Ledoux S. Ellis H.M. Horvitz H.R. Cell. 1993; 19: 641-652Abstract Full Text PDF Scopus (2238) Google Scholar, 2Cerretti D.P. Kozolosky C.J. Mosley B. Nelson N. Van Ness K. Greenstreet T.A. March C.J. Kronheim S.R. Druck T. Cannizzaro L.A. Huebner K. Black R.A. Science. 1992; 256: 97-100Crossref PubMed Scopus (994) Google Scholar, 3Thornberry N.A. Bull H.G. Calaycay J.R. Chapman K.T. Howard A.D. Kostura M.J. Miller D.K. Molineaux S.M. Weidner J.R. Aunins J. Wlliston K.O. Ayala J.M. Casano F.J. Chin J. Ding G.J.-F. Egger L.A. Gaffney E.P. Limjuco G. Palyha O.C. Raju S.M. Rolando A.M. Salley J.P. Yamin T.-T. Lee T.D. Shively J.E. MacCross M. Mumford R.A. Schmidt J.A. Tocci M.J. Nature. 1992; 356: 768-774Crossref PubMed Scopus (2194) Google Scholar). This seminal finding delineated the first two members of the caspase family and suggested that these proteinases might function during apoptosis. Subsequent studies identified over a dozen caspase family members important for apoptosis and/or inflammation (Table I) (4Van de Craen M. Vandenabeele P. Declercq W. Van den Brande I. Van Loo G. Molemans F. Schotte P. Van Criekinge W. Beyaert R. Fiers W. FEBS Lett. 1997; 403: 61-69Crossref PubMed Scopus (186) Google Scholar, 5Humke E.W. Ni J. Dixit V.M. J. Biol. Chem. 1998; 273: 15702-15707Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Shimin H. Snipas S.J. Vincenz C. Salvesen G. Dixit V.M. J. Biol. Chem. 1998; 273: 29648-29653Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar) (reviewed in Refs. 7Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4112) Google Scholar and 8Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar).Table ICaspase characteristicsZymogenProdomain, length and motifActive subunitsActivation adapterTetrapeptide preference1-aAdapted from Ref. 21.kDakDaApoptotic initiatorsCaspase-2 (51)Long, CARD20 /12RAIDDDXXD1-bThe tetrapeptides are listed in the P4–P1direction. Proteolysis occurs solely after the P1 aspartate.,1-cX denotes subsites with broad amino acid specificity.Caspase-8 (55)Long, DED18 /11FADD(L/V/D)EXD1-dWhen more than one amino acid is listed for a given subsite, each amino acid possibility is listed in order of preference.Caspase-9 (45)Long, CARD17 /10APAF-1(I/V/L)EHDCaspase-10 (55)Long, DED17 /12FADDUnknownApoptotic executionersCaspase-3 (32)Short17 /12NA1-eNA, not applicable.DEXDCaspase-6 (34)Short18 /11NA(V/T/I)EXDCaspase-7 (35)Short20 /12NADEXDCytokine processorsCaspase-1 (45)Long, CARD20 /10?CARDIAK(W/Y/F)EHDCaspase-4 (43)Long, CARD20 /10Unknown(W/L/F)EHDCaspase-5 (48)Long20 /10Unknown(W/L/F)EHDmCaspase-111-fm denotes murine.(42)Long20 /10UnknownUnknownmCaspase-12 (50)Long20 /10UnknownUnknownCaspase-13 (43)Long20 /10UnknownUnknownmCaspase-14 (30)Short20 /10NAUnknownInvertebrate caspasesCED-3 (56)Long, CARD17 /14CED-4DEXDDCP-1gDrosophila caspase-1. (36)Short22 /13NAUnknowna Adapted from Ref. 21Thornberry N.A. Rano T.A. Peterson E.P. Rasper D.M. Timkey T. Garcia-Calvo M. Houtzager V.M. Nordstrom P.A. Roy S. Vaillancourt J.P. Chapman K.T. Nicholson D.W. J. Biol. Chem. 1997; 272: 17907-17911Abstract Full Text Full Text PDF PubMed Scopus (1842) Google Scholar.b The tetrapeptides are listed in the P4–P1direction. Proteolysis occurs solely after the P1 aspartate.c X denotes subsites with broad amino acid specificity.d When more than one amino acid is listed for a given subsite, each amino acid possibility is listed in order of preference.e NA, not applicable.f m denotes murine.g Drosophila caspase-1. Open table in a new tab Several lines of evidence indicate that caspases are important for apoptosis. First, caspase activation correlates with the onset of apoptosis and caspase inhibition attenuates apoptosis (7Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4112) Google Scholar, 8Nicholson D.W. Thornberry N.A. Trends Biochem. 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Animals deficient in caspase-3, caspase-8, or caspase-9 die perinatally because of profound defects in developmental programmed cell deaths (12Green D.R. Cell. 1998; 94: 695-698Abstract Full Text Full Text PDF PubMed Scopus (1096) Google Scholar, 13Varfolomeev E.E. Schuchmann M. Luria V. Chiannikulchai N. Beckmann J.S. Mett I.L. Rebrikov D. Brodianski V.M. Kemper O.C. Kollet O. Lapidot T. Soffer D. Sobe T. Avraham K.B. Boncharov T. Holtmann H. Lonai P. Wallach D. Immunity. 1998; 9: 267-276Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar). Similarly, deletion of the gene for Drosophilacaspase-1 causes larval lethality and also promotes melanotic tumor development (14Song Z. McCall K. Stellar H. Science. 1997; 275: 536-540Crossref PubMed Scopus (249) Google Scholar). Caspase-2-deficient mice develop normally, but cells from these animals show diminished or enhanced apoptosis, depending on their tissue of origin (15Bergeron L. Perez G.I. Macdonald G. Shi L. Sun Y. Jurisicova A. Varmuza S. Latham K.E. Flaws J.A. Salter J.C.M. Hara H. Moskowitz M.A. Li W. Greenberg A. Tilly J.L. Yuan J. Genes Dev. 1998; 12: 1304-1314Crossref PubMed Scopus (600) Google Scholar). These differences may relate to tissue-specific expression of pro- and anti-apoptotic caspase-2 isoforms. By contrast, caspase-1 and caspase-11 knockout mice have defective interleukin-1β production but develop normally and have minimal apoptotic defects (12Green D.R. Cell. 1998; 94: 695-698Abstract Full Text Full Text PDF PubMed Scopus (1096) Google Scholar, 16Wang S. Miura M. Jung Y. Zhu H. Li E. Yuan J. Cell. 1998; 92: 501-509Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar). Sequence analysis and x-ray crystallography data suggest that all caspases share a common structure (4Van de Craen M. Vandenabeele P. Declercq W. Van den Brande I. Van Loo G. Molemans F. Schotte P. Van Criekinge W. Beyaert R. Fiers W. FEBS Lett. 1997; 403: 61-69Crossref PubMed Scopus (186) Google Scholar, 5Humke E.W. Ni J. Dixit V.M. J. Biol. Chem. 1998; 273: 15702-15707Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Shimin H. Snipas S.J. Vincenz C. Salvesen G. Dixit V.M. J. Biol. Chem. 1998; 273: 29648-29653Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 7Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4112) Google Scholar, 8Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar, 17Walker N.P.C. Talanian R.V. Brady K.D. Dang L.C. Bump N.J. Ferenz C.R. Franklin S. Ghayur T. Hackett M.C. Hammil L.D. Herzog L. Hugunin M. Houy W. Mankovich J.A. McGuiness L. Oriewicz E. Paskind M. Pratt C.A. Reis P. Summani A. Terranova M. Welch J.P. Xiong L. Moller A. Tracey D.E. Kamen R. Wong W.W. Cell. 1994; 78: 343-352Abstract Full Text PDF PubMed Scopus (527) Google Scholar, 18Wilson K.P. Black J.F. Thomson J.A. Kim E.E. Griffith J.P. Navia M.A. Murcko M.A. Chambers S.P. Aldape R.A. Raybuck S.A. Livingston D.J. Nature. 1994; 370: 270-275Crossref PubMed Scopus (753) Google Scholar, 19Rotonda J. Nicholson D.W. Fazil K.M. Gallant M. Gareau Y. Labelle M. Peterson E.P. Rasper D.M. Ruel R. Vaillancourt J.P. Thornberry N.A. Becker J.W. Nature Biotechnol. 1996; 3: 619-625Google Scholar, 20Mittl P.R.E. Di Marco S. Krebs J.F. Bai X. Karanewsky D.S. Priestle J.P. Tomaselli K.J. Grutter M.G. J. Biol. Chem. 1997; 272: 6539-6547Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). Each zymogen contains an N-terminal prodomain, a large subunit containing the active site cysteine within a conserved QACXG motif, and a C-terminal small subunit. An aspartate cleavage site separates the prodomain from the large subunit, and an interdomain linker containing one or two aspartate cleavage sites separates the large and small subunits. Activation accompanies proteolysis of the interdomain linker and usually results in subsequent removal of the prodomain. The active enzymes function as tetramers, consisting of two large/small subunit heterodimers (17Walker N.P.C. Talanian R.V. Brady K.D. Dang L.C. Bump N.J. Ferenz C.R. Franklin S. Ghayur T. Hackett M.C. Hammil L.D. Herzog L. Hugunin M. Houy W. Mankovich J.A. McGuiness L. Oriewicz E. Paskind M. Pratt C.A. Reis P. Summani A. Terranova M. Welch J.P. Xiong L. Moller A. Tracey D.E. Kamen R. Wong W.W. Cell. 1994; 78: 343-352Abstract Full Text PDF PubMed Scopus (527) Google Scholar, 18Wilson K.P. Black J.F. Thomson J.A. Kim E.E. Griffith J.P. Navia M.A. Murcko M.A. Chambers S.P. Aldape R.A. Raybuck S.A. Livingston D.J. Nature. 1994; 370: 270-275Crossref PubMed Scopus (753) Google Scholar, 19Rotonda J. Nicholson D.W. Fazil K.M. Gallant M. Gareau Y. Labelle M. Peterson E.P. Rasper D.M. Ruel R. Vaillancourt J.P. Thornberry N.A. Becker J.W. Nature Biotechnol. 1996; 3: 619-625Google Scholar, 20Mittl P.R.E. Di Marco S. Krebs J.F. Bai X. Karanewsky D.S. Priestle J.P. Tomaselli K.J. Grutter M.G. J. Biol. Chem. 1997; 272: 6539-6547Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). The heterodimers each contain an active site composed of residues from both the small and large subunits. Each active site contains a positively charged S1 subsite that binds the substrate's negatively charged P1 aspartate (17Walker N.P.C. Talanian R.V. Brady K.D. Dang L.C. Bump N.J. Ferenz C.R. Franklin S. Ghayur T. Hackett M.C. Hammil L.D. Herzog L. Hugunin M. Houy W. Mankovich J.A. McGuiness L. Oriewicz E. Paskind M. Pratt C.A. Reis P. Summani A. Terranova M. Welch J.P. Xiong L. Moller A. Tracey D.E. Kamen R. Wong W.W. Cell. 1994; 78: 343-352Abstract Full Text PDF PubMed Scopus (527) Google Scholar, 18Wilson K.P. Black J.F. Thomson J.A. Kim E.E. Griffith J.P. Navia M.A. Murcko M.A. Chambers S.P. Aldape R.A. Raybuck S.A. Livingston D.J. Nature. 1994; 370: 270-275Crossref PubMed Scopus (753) Google Scholar, 19Rotonda J. Nicholson D.W. Fazil K.M. Gallant M. Gareau Y. Labelle M. Peterson E.P. Rasper D.M. Ruel R. Vaillancourt J.P. Thornberry N.A. Becker J.W. Nature Biotechnol. 1996; 3: 619-625Google Scholar, 20Mittl P.R.E. Di Marco S. Krebs J.F. Bai X. Karanewsky D.S. Priestle J.P. Tomaselli K.J. Grutter M.G. J. Biol. Chem. 1997; 272: 6539-6547Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). This S1 binding site is highly conserved; therefore, all caspases cleave solely after aspartate residues. The individual caspases have two major structural differences. First, the predicted S2–S4 substrate binding sites vary significantly, resulting in varied substrate specificity in the P2–P4 positions, despite an absolute requirement for aspartate in the P1 position (4Van de Craen M. Vandenabeele P. Declercq W. Van den Brande I. Van Loo G. Molemans F. Schotte P. Van Criekinge W. Beyaert R. Fiers W. FEBS Lett. 1997; 403: 61-69Crossref PubMed Scopus (186) Google Scholar, 5Humke E.W. Ni J. Dixit V.M. J. Biol. Chem. 1998; 273: 15702-15707Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Shimin H. Snipas S.J. Vincenz C. Salvesen G. Dixit V.M. J. Biol. Chem. 1998; 273: 29648-29653Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 7Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4112) Google Scholar, 8Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar,17Walker N.P.C. Talanian R.V. Brady K.D. Dang L.C. Bump N.J. Ferenz C.R. Franklin S. Ghayur T. Hackett M.C. Hammil L.D. Herzog L. Hugunin M. Houy W. Mankovich J.A. McGuiness L. Oriewicz E. Paskind M. Pratt C.A. Reis P. Summani A. Terranova M. Welch J.P. Xiong L. Moller A. Tracey D.E. Kamen R. Wong W.W. Cell. 1994; 78: 343-352Abstract Full Text PDF PubMed Scopus (527) Google Scholar, 18Wilson K.P. Black J.F. Thomson J.A. Kim E.E. Griffith J.P. Navia M.A. Murcko M.A. Chambers S.P. Aldape R.A. Raybuck S.A. Livingston D.J. Nature. 1994; 370: 270-275Crossref PubMed Scopus (753) Google Scholar, 19Rotonda J. Nicholson D.W. Fazil K.M. Gallant M. Gareau Y. Labelle M. Peterson E.P. Rasper D.M. Ruel R. Vaillancourt J.P. Thornberry N.A. Becker J.W. Nature Biotechnol. 1996; 3: 619-625Google Scholar, 20Mittl P.R.E. Di Marco S. Krebs J.F. Bai X. Karanewsky D.S. Priestle J.P. Tomaselli K.J. Grutter M.G. J. Biol. Chem. 1997; 272: 6539-6547Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). Thornberry et al. (21Thornberry N.A. Rano T.A. Peterson E.P. Rasper D.M. Timkey T. Garcia-Calvo M. Houtzager V.M. Nordstrom P.A. Roy S. Vaillancourt J.P. Chapman K.T. Nicholson D.W. J. Biol. Chem. 1997; 272: 17907-17911Abstract Full Text Full Text PDF PubMed Scopus (1842) Google Scholar) recently defined the optimal tetrapeptide substrate specificity for 10 caspases using a synthetic combinatorial peptide library. The sequence preferences generally correlate with caspase function as apoptotic initiators, apoptotic executioners, and cytokine processors (Table I). Note that the tetrapeptide preferences listed in Table I are not absolute and that the preferences do not represent kinetic values that can be directly compared. For example, caspase-3 and caspase-7 both prefer DEXD-based peptides; however, the kinetics of the individual hydrolysis reactions may differ significantly. Second, caspase prodomains vary in length and sequence (Table I). Long prodomain caspases function as signal integrators for apoptotic or pro-inflammatory signals and contain sequence motifs that promote their interaction with activator molecules (Table I) (22Hoffman K. Bucher P. Tschopp J. Trends Biochem. Sci. 1997; 22: 155-156Abstract Full Text PDF PubMed Scopus (447) Google Scholar, 23Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5124) Google Scholar). The apoptotic initiators (caspase-2, -8, -9, and -10) generally act upstream of the small prodomain apoptotic executioners (caspase-3, -6, and -7) (7Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4112) Google Scholar, 8Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar,23Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5124) Google Scholar). By contrast, caspase-1 and caspase-11 function predominantly as cytokine processors (12Green D.R. Cell. 1998; 94: 695-698Abstract Full Text Full Text PDF PubMed Scopus (1096) Google Scholar, 16Wang S. Miura M. Jung Y. Zhu H. Li E. Yuan J. Cell. 1998; 92: 501-509Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar). Less is known about caspase-4, -5, -12, -13, and -14; however, these caspases demonstrate a higher degree of sequence similarity to caspase-1 than to the apoptotic caspases (4Van de Craen M. Vandenabeele P. Declercq W. Van den Brande I. Van Loo G. Molemans F. Schotte P. Van Criekinge W. Beyaert R. Fiers W. FEBS Lett. 1997; 403: 61-69Crossref PubMed Scopus (186) Google Scholar, 5Humke E.W. Ni J. Dixit V.M. J. Biol. Chem. 1998; 273: 15702-15707Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Shimin H. Snipas S.J. Vincenz C. Salvesen G. Dixit V.M. J. Biol. Chem. 1998; 273: 29648-29653Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 7Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4112) Google Scholar, 8Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar). Therefore, these caspases are grouped with the cytokine processors. Overall, caspase substrate specificity, prodomain length, and prodomain sequence determine caspase function. Because caspases exist as latent zymogens, the question remains as to how the zymogens are activated. Current evidence suggests that activation may proceed by autoactivation, transactivation, or proteolysis by other proteinases. Affinity-labeling experiments demonstrate that caspase zymogens have low but detectable proteolytic activity, suggesting the potential for autoactivation under certain circumstances (24Yamin T.T. Ayala J.M. Miller D.K. J. Biol. Chem. 1996; 271: 13273-13282Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 25Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar). Furthermore, overexpression of wild type caspases, but not catalytically inactive mutants, results in caspase processing and activation, indicating that autoactivation may occur at high enzyme concentration (26Orth K. O'Rourke K. Salvesen G. Dixit V.M. J. Biol. Chem. 1996; 271: 20977-20980Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). 1H. R. Stennicke and G. S. Salvesen, personal communication. Forced oligomerization of procaspase-8, procaspase-9, or CED-3 facilitates zymogen autoactivation and promotes apoptosis (25Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar, 27Martin D.A. Siegel R.M. Zheng L. Lenardo M.J. J. Biol. Chem. 1998; 273: 4345-4349Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 28Yang X. Chang H.Y. Baltimore D. Mol. Cell. 1998; 1: 319-325Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar, 29Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Alnemri E.S. Mol. Cell. 1998; 1: 949-957Abstract Full Text Full Text PDF PubMed Scopus (962) Google Scholar, 30Yang X. Chang H.Y. Baltimore D. Science. 1998; 281: 1355-1357Crossref PubMed Scopus (234) Google Scholar). This process may approximate zymogens and restrict their mobility, thereby increasing the local enzyme concentration and promoting autoactivation. In vivo, adapter molecules mediate oligomerization of long prodomain procaspases. Adapter molecules link apoptotic sensors such as death receptors and mitochondria to procaspases. To accomplish this, adapters generally contain one domain that couples the adapter to the sensor and another that binds to long prodomain procaspases. These domains include death domains (DDs), 2The abbreviations DDdeath domainDEDdeath effector domainCARDcaspase recruitment domainFADDFas-associated death domainRAIDDRip-associated ICH-1/CED-3 homologous protein with a death domainAPAF-1apoptotic protease-activating factor-1CARDIAKCARD-containing interleukin-1β converting enzyme-associated kinaseCADcaspase-activated DNaseICADinhibitor of caspase-activated DNasePAK2p21-activated kinase 2MEKK1mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1PKCprotein kinase CNuManuclear mitotic apparatus proteinSAF-Ascaffold attachment factor AGas2growth arrest specific gene 2FAKfocal adhesion kinase death effector domains (DEDs), and caspase recruitment domains (CARDs) (TableI). DDs, DEDs, and CARDs all contain six anti-parallel α-helices arranged in a similar three-dimensional fold and associate via like-like interactions (31Huang B. Eberstadt M. Olejniczak E.T. Meadows R.P. Fesik S.W. Nature. 1996; 384: 638-641Crossref PubMed Scopus (319) Google Scholar, 32Eberstadt M. Huang B. Chen Z. Meadows R.P. Ng S.-C. Zheng L. Lenardo M.J. Fesik S.W. Nature. 1998; 392: 941-945Crossref PubMed Scopus (204) Google Scholar, 33Chou J.J. Matsuo H. Duan H. Wagner G. Cell. 1998; 94: 171-180Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). However, hydrophobic interactions are important for DED-DED interactions, whereas electrostatic interactions are critical for CARD-CARD interactions (31Huang B. Eberstadt M. Olejniczak E.T. Meadows R.P. Fesik S.W. Nature. 1996; 384: 638-641Crossref PubMed Scopus (319) Google Scholar, 32Eberstadt M. Huang B. Chen Z. Meadows R.P. Ng S.-C. Zheng L. Lenardo M.J. Fesik S.W. Nature. 1998; 392: 941-945Crossref PubMed Scopus (204) Google Scholar, 33Chou J.J. Matsuo H. Duan H. Wagner G. Cell. 1998; 94: 171-180Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). death domain death effector domain caspase recruitment domain Fas-associated death domain Rip-associated ICH-1/CED-3 homologous protein with a death domain apoptotic protease-activating factor-1 CARD-containing interleukin-1β converting enzyme-associated kinase caspase-activated DNase inhibitor of caspase-activated DNase p21-activated kinase 2 mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 protein kinase C nuclear mitotic apparatus protein scaffold attachment factor A growth arrest specific gene 2 focal adhesion kinase The adapter molecule FADD couples the Fas death receptor to procaspase-8. FADD contains a DD that interacts with a similar domain on Fas and also contains a DED that binds to the DEDs of procaspase-8 (23Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5124) Google Scholar). Fas activation stimulates binding of the receptor's DD to the corresponding domain in FADD, which in turn recruits procaspase-8 by a homophilic interaction involving DEDs. Subsequent oligomerization then promotes procaspase-8 autoactivation (Fig.1) (23Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5124) Google Scholar, 34Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2727) Google Scholar, 35Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2102) Google Scholar). FADD probably activates procaspase-10 through a similar mechanism (36Vincenz C. Dixit V.M. J. Biol. Chem. 1997; 272: 6578-6583Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). Interestingly, FLIP, a catalytically inactive caspase-8-like molecule with two DEDs, inhibits Fas-FADD-procaspase-8 interactions and thereby inhibits apoptosis (37Irmler M. Thome M. Hahne M. Schneider P. Hofmann K. Steiner V. Bodmer J.L. Schreoter M. Burns K. Mattmann C. Rimoldi D. French L.E. Tschopp J. Nature. 1997; 388: 190-195Crossref PubMed Scopus (2217) Google Scholar). Mitochondria sense apoptotic signals and convey them to the activation adapter APAF-1 via the release of cytochrome c. Cytochromec binds to APAF-1, and in the presence of adenine nucleotides, the APAF-1-cytochrome c complex promotes activation of procaspase-9 (38Li P. Nijhawan D. Budihardjo I. Srinivasula S.M. Ahmad M. Alnemri E.S. Wang X. Cell. 1997; 91: 470-489Abstract Full Text Full Text PDF Scopus (6197) Google Scholar). Cytochrome c and adenine nucleotides likely induce a conformational change that exposes the APAF-1 CARD domain. The exposed APAF-1 CARD domain can in turn recruit procaspase-9 by a homophilic interaction involving CARDs. Subsequent procaspase-9 oligomerization then facilitates caspase autoactivation. Bcl-XL, an anti-apoptotic Bcl-2 family protein, may inhibit apoptosis by blocking these interactions (39Hu Y. Benedict M.A. Wu D. Inohara N. Nunez G. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4386-4391Crossref PubMed Scopus (496) Google Scholar). A second CARD-containing adapter, RAIDD, couples procaspase-2 to death receptors via CARD-CARD interactions (40Duan H. Dixit V.M. Nature. 1997; 385: 86-89Crossref PubMed Scopus (469) Google Scholar, 41Ahmad M. Srinivasula S.M. Wang L. Talanian R.V. Litwack G. Fernandes-Alnemri T. Alnemri E.S. Cancer Res. 1997; 57: 615-619PubMed Google Scholar). Thus, adapter-mediated protein-protein interactions are widespread among the apoptotic caspases. Less is known about activation of pro-inflammatory caspases. CARDIAK, a CARD-containing kinase, promotes procaspase-1 activation in vitro via a CARD-CARD interaction, suggesting that CARD-mediated oligomerization could function in procaspase-1 activation (42Thome M. Hofmann K. Burns K. Martinon F. Bodmer J.-L. Mattmann C. Tschopp J. Curr. Biol. 1998; 8: 885-888Abstract Full Text Full Text PDF PubMed Google Scholar). Ligation of the CD40 receptor also promotes procaspase-1 activation (43Schonbeck U. Mach F. Bonnefoy J.-Y. Loppnow H. Flad H.-D. Libby P. J. Biol. Chem. 1997; 272: 19569-19574Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar); however, whether CARDIAK facilitates this activation is unknown. Finally, caspase-11 does not directly process procaspase-1 but may facilitate zymogen activation by a non-proteolytic interaction (16Wang S. Miura M. Jung Y. Zhu H. Li E. Yuan J. Cell. 1998; 92: 501-509Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar). Once activated, caspases transactivate other procaspases, providing the opportunity for cascade amplification and positive feedback. Caspase-8 for example efficiently activates procaspase-3 (k cat/Km = 8.7 × 105m–1 s–1) (44Stennicke H.R. Jurgensmeier J.M. Shin H. Deveraux Q. Wolf B.B. Yang X. Zhou Q. Ellerby H.M. Ellerby L.M. Bredesen D. Green D.R. Reed J.C. Froelich C.J. Salvesen G.S. J. Biol. Chem. 1998; 273: 27084-27090Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar), and active caspase-3 in turn may activate procaspase-8. Although this positive feedback loop is theoretically possible, it has not yet been demonstrated. Additionally, because caspases have varied substrate specificity, a single activated caspase may not directly activate all other family members. For example, caspase-9 activates procaspase-3 and procaspase-7 but cannot activate procaspase-6 (29Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Alnemri E.S. Mol. 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Remarkably, granzyme B activates procaspase-3 5.5 times faster than caspase-8 and 17 times faster than caspase-10 (44Stennicke H.R. Jurgensmeier J.M. Shin H. Deveraux Q. Wolf B.B. Yang X. Zhou Q. Ellerby H.M. Ellerby L.M. Bredesen D. Green D.R. Reed J.C. Froelich C.J. Salvesen G.S. J. Biol. Chem. 1998; 273: 27084-27090Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). A second serine proteinase, cathepsin G, efficiently activates procaspase-7 by cleaving after Gln-194, indicating that aspartate specificity is not required for caspase activatio