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The Caspase Family of Proteins

The Caspase Family of Proteins. C ysteine-dependent A spartate- S pecific P rote ase s. Outline. Overview 2 main classes of Caspases Regulation Activation Caspase Cascade Consequences of the Cascade References. Overview of Caspase. Cysteine proteases

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The Caspase Family of Proteins

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  1. The Caspase Family of Proteins Cysteine-dependent Aspartate-Specific Proteases

  2. Outline • Overview • 2 main classes of Caspases • Regulation • Activation • Caspase Cascade • Consequences of the Cascade • References

  3. Overview of Caspase • Cysteine proteases • Have critical cysteine in active site - if mutated activity is lost • Cleave after aspartic residue • endoproteases- that are integral to cell death • Exist as inactive precursors until activation • Cascade similar to blood clotting factors

  4. Overview Thornberry, N.A. & Lazebnik, Y. (1998) Science 281: 1312-1316

  5. Initiator-upstream activator activates effector caspases Effector executioners in cell cleave proteins that induce apoptosis Two Main Classes

  6. Regulation • Since these proteins are “killers” they are highly regulated • Need to be ready for quick activation • Regulated at post-transcriptional level • exist in cytoplasm as immature procaspases

  7. Activation • Exist as immature pro-caspases • Three basic procaspase domains • Prodomain • large subunit • small subunit • prodomain • Initiator caspases have large prodomain • Effector caspases have small prodomain

  8. Procaspase Cleavage sites Asp Asp Inactive procaspase precursor H2N COOH Cleavage generates two subunits Prodomain Large Subunit Raff, M. (1998). Nature 396: 119. Small Subunit Subunits assemble into active enzyme Adapted from Raff, 1998

  9. After Cleavage • The large and small subunits come together to form a heterodimer • Then the two heterodimers come together to form a tetramer

  10. Caspase Cascade activation • Ratio of (pro-apoptotic Bcl2/ prosurvival Bcl2) regulates the release of Cyt-C from the Mitochondria • Cyt C (and ATP of dATP) binds to Apaf-1 leading to activation • Apaf-1 then oligomerize by binding to the predomains of procaspase-9

  11. Caspase activation continued • This brings pro-caspase-9 in close proximity to each other • Procaspase-9 then cleave each other • This leads to the formation of mature caspase-9 (tetramer w/ 2 large subunits and 2 small subunits) • Now mature caspase 9 cleaves and activates effector caspase

  12. Caspases Activating Caspases Slee et al. (1999) Journal of Cell Biology 144: 281-291.

  13. Consequences of the Cascade • Effector caspases not only cleave other caspase but can cleave other cellular substrates that lead to morphological features associated with apoptosis • This insure that the caspase cascade leads to irreversible cell suicide

  14. Examples Thornberry, N.A. & Lazebnik, Y. (1998) Science 281: 1312-1316

  15. References • http://www.colorado.edu/MCDB/MCDB4620/15ppt.pdf • H. Yoshida et al. “Apaf 1 is required for mitochondrial pathways in apoptosis and brain development” Cell, 94:739-50, 1998. • M. Woo et al., “Essential contributions of caspase 3/CPP32 to apoptosis and its associated nuclear changes” Genes and Development, 12:806-19 • Reed, John C. “Methods in Enzymology Volume 322 Apoptosis” Academic Press; 2000. • http://www.geocities.com/CollegePark/Lab/1580/caspase.html • http://iai.asm.org/cgi/content/full/70/1/55 • Slee et al. (1999) Journal of Cell Biology 144: 281-291 • Thornberry, N.A. & Lazebnik, Y. (1998) Science 281: 1312-1316

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