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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

The Caspase Family of Proteins

Cysteine-dependent Aspartate-Specific Proteases

outline
Outline
  • Overview
  • 2 main classes of Caspases
  • Regulation
  • Activation
  • Caspase Cascade
  • Consequences of the Cascade
  • References
overview of caspase
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
overview
Overview

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

two main classes
Initiator-upstream activator

activates effector caspases

Effector executioners in cell

cleave proteins that induce apoptosis

Two Main Classes
regulation
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
activation
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
procaspase
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

after cleavage
After Cleavage
  • The large and small subunits come together to form a heterodimer
  • Then the two heterodimers come together to form a tetramer
caspase cascade activation
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
caspase activation continued
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
caspases activating caspases
Caspases Activating Caspases

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

consequences of the cascade
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
examples
Examples

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

references
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