Taxonomic distribution of proteins containing CASc domains

The CASc domain within your query sequence starts at position 190 and ends at position 402, and its E-value is 6.58e-52.

Three-dimensional structures of proteins involved in programmed cell death.

Liang H, Fesik SW
J Mol Biol. 1997; 274: 291-302

Programmed cell death (apoptosis) is a controlled process by which unwanted cells are selectively eliminated. Several families of proteins including the Bcl-2, tumor necrosis factor receptor 1, and caspase families play essential roles in the regulation, signaling, and execution of the genetic cell death program. The recently described three-dimensional structures of members of these families elucidate the structural basis of their functions and provide insights into the mechanisms by which these proteins regulate apoptosis.

The interleukin-1 beta converting enzyme family of cysteine proteases.

Miller DK, Myerson J, Becker JW
J Cell Biochem. 1997; 64: 2-10

Interleukin-1 beta converting enzyme (ICE) is the first enzyme of a new family of cysteine endoproteinases to be isolated and characterized. An overview of the structure and activity of ICE is outlined together with highlights of salient features common to members of each of the family members.

Caspases and caspase inhibitors.

Villa P, Kaufmann SH, Earnshaw WC
Trends Biochem Sci. 1997; 22: 388-93

Five years ago, little was known about mechanisms of apoptotic execution. Now, one class of cell-death gene, the cysteine and aspartases (caspases) has come under intensive study. This review discusses the two classes of caspases, the reasons why humans may have so many caspase genes, the growing list of caspase substrates, and viral and pharmacological caspase inhibitors.

Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition.

Komiyama T, Ray CA, Pickup DJ, Howard AD, Thornberry NA, Peterson EP, Salvesen G
J Biol Chem. 1994; 269: 19331-7

We reported previously that human interleukin-1 beta converting enzyme (ICE) is regulated by the CrmA serpin encoded by cowpox virus. We now report the mechanism and kinetics of this unusual inhibition of a cysteine proteinase by a member of the serpin superfamily previously thought to inhibit serine proteinase only. CrmA possesses several characteristics typical of a number of inhibitory serpins. It is conformationally unstable, unfolding around 3 M urea, and stable to denaturation in 8 M urea upon complex formation with ICE. CrmA rapidly inhibits ICE with an association rate constant (kon) of 1.7 x 10(7) M-1 s-1, forming a tight complex with an equilibrium constant for inhibition (Ki) of less than 4 x 10(-12) M. These data indicate that CrmA is a potent inhibitor of ICE, consistent with the dramatic effects of CrmA on modifying host responses to virus infection. The inhibition of ICE by CrmA is an example of a "cross-class" interaction, in which a serpin inhibits a non-serine proteinase. Since CrmA possesses characteristics shared by inhibitors of serine proteinases, we presume that ICE, though it is a cysteine proteinase, has a substrate binding geometry strikingly close to that of serine proteinases. We reason that it is the substrate binding geometry, not the catalytic mechanism of a proteinase, that dictates its reactivity with protein inhibitors.

Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer.

Walker NP, Talanian RV, Brady KD, Dang LC, Bump NJ, Ferenz CR, Franklin S, Ghayur T, Hackett MC, Hammill LD, etal.
Cell. 1994; 78: 343-52

Interleukin-1 beta-converting enzyme (ICE) proteolytically cleaves pro-IL-1 beta to its mature, active form. The crystal structure at 2.5 A resolution of a recombinant human ICE-tetrapeptide chloromethylketone complex reveals that the holoenzyme is a homodimer of catalytic domains, each of which contains a p20 and a p10 subunit. The spatial separation of the C-terminus of p20 and the N-terminus of p10 in each domain suggests two alternative pathways of assembly and activation in vivo. ICE is homologous to the C. elegans cell death gene product, CED-3, and these may represent a novel class of cytoplasmic cysteine proteases that are important in programmed cell death (apoptosis). Conservation among members of the ICE/CED-3 family of the amino acids that form the active site region of ICE supports the hypothesis that they share functional similarities.

Structure and mechanism of interleukin-1 beta converting enzyme.

Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA, etal.
Nature. 1994; 370: 270-5

Interleukin-1 beta converting enzyme (ICE) processes an inactive precursor to the proinflammatory cytokine, interleukin-1 beta, and may regulate programmed cell death in neuronal cells. The high-resolution structure of human ICE in complex with an inhibitor has been determined by X-ray diffraction. The structure confirms the relationship between human ICE and cell-death proteins in other organisms. The active site spans both the 10 and 20K subunits, which associate to form a tetramer, suggesting a mechanism for ICE autoactivation.

Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3.

Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J
Cell. 1993; 75: 653-60

The mammalian interleukin-1 beta-converting enzyme (ICE) has sequence similarity to the C. elegans cell death gene ced-3. We show here that overexpression of the murine ICE (mICE) gene or of the C. elegans ced-3 gene causes Rat-1 cells to undergo programmed cell death. Point mutations in a region homologous between mICE and CED-3 eliminate the ability of mICE and ced-3 to cause cell death. The cell death caused by mICE can be suppressed by overexpression of the crmA gene, a specific inhibitor of ICE, as well as by bcl-2, a mammalian oncogene that can act to prevent programmed cell death. Our results suggest that ICE may function during mammalian development to cause programmed cell death.

The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme.

Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR
Cell. 1993; 75: 641-52

We have cloned the C. elegans cell death gene ced-3. A ced-3 transcript is most abundant during embryogenesis, the stage during which most programmed cell deaths occur. The predicted CED-3 protein shows similarity to human and murine interleukin-1 beta-converting enzyme and to the product of the mouse nedd-2 gene, which is expressed in the embryonic brain. The sequences of 12 ced-3 mutations as well as the sequences of ced-3 genes from two related nematode species identify sites of potential functional importance. We propose that the CED-3 protein acts as a cysteine protease in the initiation of programmed cell death in C. elegans and that cysteine proteases also function in programmed cell death in mammals.

Molecular cloning of the interleukin-1 beta converting enzyme.

Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, VanNess K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA, etal.
Science. 1992; 256: 97-100

Interleukin-1 beta (IL-1 beta) mediates a wide range of immune and inflammatory responses. The active cytokine is generated by proteolytic cleavage of an inactive precursor. A complementary DNA encoding a protease that carries out this cleavage has been cloned. Recombinant expression in COS-7 cells enabled the cells to process precursor IL-1 beta to the mature form. Sequence analysis indicated that the enzyme itself may undergo proteolytic processing. The gene encoding the protease was mapped to chromosomal band 11q23, a site frequently involved in rearrangement in human cancers.

A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.

Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J, etal.
Nature. 1992; 356: 768-74

Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target.