Preparation of an Autolysis-Resistant Interleukin-1β Converting Enzyme Mutant

Dang, Luan C.; Talanian, Robert V.; Banach, David; Hackett, Maria; Gilmore, John L.; Hays, Samuel P.; Mankovich, John A.; Brady, Kenneth D.

doi:10.1021/bi9617771

Cited by 21 publications

(17 citation statements)

References 18 publications

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“…Enzyme Expression and Purification-Caspase-1, -2, -3, and -4, containing N-terminal His tags to facilitate purification, were prepared as described (9,30,47). Caspase-1 contained the stability-enhancing point mutation D381E (47).…”

Section: Methodsmentioning

confidence: 99%

“…Caspase-1 contained the stability-enhancing point mutation D381E (47). Caspase-6 (Mch2␣) (11) beginning at Ala-2, or * The costs of publication of this article were defrayed in part by the payment of page charges.…”

Section: Methodsmentioning

confidence: 99%

“…Simultaneous expression of the chaperones and proteases were induced by addition of isopropyl-1-thio-␤-D-galactopyranoside to 2 mM and temperature shift from 30°C to 40°C at A 600 ϭ 0.6. The bacteria were harvested at t ϭ 5 h, and the proteases were purified as described (47).…”

Section: Methodsmentioning

confidence: 99%

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Substrate Specificities of Caspase Family Proteases

Talanian¹,

Quinlan²,

Trautz³

et al. 1997

Journal of Biological Chemistry

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834

654

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The caspase family represents a new class of intracellular cysteine proteases with known or suspected roles in cytokine maturation and apoptosis. These enzymes display a preference for Asp in the P1 position of substrates. To clarify differences in the biological roles of the interleukin-1␤ converting enzyme (ICE) family proteases, we have examined in detail the specificities beyond the P1 position of caspase-1, -2, -3, -4, -6, and -7 toward minimal length peptide substrates in vitro. We find differences and similarities between the enzymes that suggest a functional subgrouping of the family different from that based on overall sequence alignment. The primary specificities of ICE homologs explain many observed enzyme preferences for macromolecular substrates and can be used to support predictions of their natural function(s). The results also suggest the design of optimal peptidic substrates and inhibitors.A growing body of evidence supports important roles for the interleukin-1␤ converting enzyme (ICE) 1 (1, 2) and its homologs (recently renamed caspases (3)) in cytokine maturation and apoptosis. The caspase gene family, defined by protein sequence homology but also characterized by conservation of key catalytic and substrate-recognition amino acids, includes caspase-2 (4), caspase-3 (5-7), caspase-4 (8 -10), caspase-5 (10), caspase-6 (11), caspase-7 (12-14), caspase-8 (15-17), caspase-9 (18, 19), and caspase-10 (17). Each is an intracellular cysteine protease that shares with the serine protease granzyme B specificity for Asp in the P1 position of substrates. The specific biological roles and interrelationships of these enzymes are for the most part unknown and are areas of active investigation in many laboratories.A role for caspase-1 in inflammation is supported by several lines of evidence. Caspase-1-deficient mice, and cells derived from those animals, are deficient in IL-1␤ maturation and are resistant to endotoxic shock (20,21). Peptidic inhibitors of caspase-1 can be effective in blocking maturation and release of IL-1␤ by cultured cells (1) and in whole animals (22, 23) and of inflammation in animal models (24,25). The selectivity of the inhibitors employed in these studies among the caspases has not been demonstrated, and so the precise role of each caspase in inflammation is uncertain. Nevertheless the results uphold the promise of caspase-1 and/or its homologs as targets for anti-inflammatory drug discovery.Caspases play important roles in apoptosis signaling and effector mechanisms. Sequence alignments reveal homology with Ced-3 (26), a nematode cysteine protease (27, 28) that is required for cell death. The viral proteins CrmA and p35 are antiapoptotic and act by inhibition of caspases (29,30). A bacterial invasin induces apoptosis by binding to and activating caspase-1 specifically (31). Caspase-3 is necessary and sufficient for apoptosis in one acellular model (6); however, in mice the essential function of this enzyme is limited to apoptosis in the brain (32). A hallmark of apoptosis is the pr...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Substrate Specificities of Caspase Family Proteases

Talanian¹,

Quinlan²,

Trautz³

et al. 1997

Journal of Biological Chemistry

Self Cite

834

654

View full text Add to dashboard Cite

show abstract

“…Caspase 1 contained the stability-enhancing point mutation D381E (Dang et al 1996). The tetrapeptide inhibitors acetylTyr-Val-Ala-Asp-aldehyde (Ac-YVAD-cho) and acetyl-AspGlu-Val-Asp-aldehyde (Ac-DEVD-cho) were purchased from the Peptide Institute (Osaka, Japan), while acetyl-Val-Glu-ValAsp-aldehyde (Ac-VEVD-cho) was custom-synthesized at the Peptide Institute.…”

Section: Recombinant Caspases Substrates and Inhibitorsmentioning

confidence: 99%

Fas‐induced DNA fragmentation and proteolysis of nuclear proteins

Kawahara

Enari²,

Talanian³

et al. 1998

Genes to Cells

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“…There are efforts to block the activities of cytokines by preventing their proteolytic processing. Parke-Davis/BASF [214] and Vertex have programs to develop inhibitors to interleukin converting enzyme (ICE) to decrease the production of IL-1β. Immunex and SmithKline Beecham are also involved in creating compounds that inhibit the proteolytic conversion of TNF-α.…”

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

Emerging strategies for the treatment of Alzheimer’s disease at the Millennium

Emmerling¹,

Spiegel²,

Hall³

et al. 1999

Emerging Drugs

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It is estimated that by the year 2050 the number of cases of Alzheimer's disease (AD) will more than triple in the United States alone. As longevity increases, AD cases are expected to skyrocket from 4 -14 m. Globally, the numbers may reach 60 -80 m. Those expected to develop AD in the next century are presently in their 20s, 30s or 40s. Thus, steps must be taken to prevent this imminent epidemic, and the emotional and economic toll that it will exact on both patients and families. Numerous new strategies to treat AD have emerged in the last decade. This is the direct result of an increased understanding of the molecular pathology associated with the development of AD dementia, as well as the harvesting of results from case-control and cohort epidemiological studies. AD is no longer viewed solely as a disease of neurotransmitter deficits or amyloid deposition. Rather, it is a combination of events (amyloidosis, neurofibrillary pathology, inflammation, oxidative stress and cerebral vascular insufficiency) that conspire to produce this dementia. This avalanche of information reveals the complexity of the genetic and environmental contributors to AD. At the same time, these advances also delineate new avenues by which AD may be palliated, halted or averted. In the present review, we shall explore the emerging opportunities for the treatment and prevention of AD. 35 1999

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Preparation of an Autolysis-Resistant Interleukin-1β Converting Enzyme Mutant

Cited by 21 publications

References 18 publications

Substrate Specificities of Caspase Family Proteases

Substrate Specificities of Caspase Family Proteases

Fas‐induced DNA fragmentation and proteolysis of nuclear proteins

Emerging strategies for the treatment of Alzheimer’s disease at the Millennium

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