Figure 7

Model depicting proposed mechanism of caspase-8 inhibition by Tyr380 phosphorylation. (a) Canonical procaspase-8 activation. (i) cytoplasmic procaspase-8 is recruited to the CD95/FADD complex at the cell-surface membrane leading to (ii) dimerization and DED-mediated caspase-8 chain assembly. This is followed by (iii) autoproteolytic cleavage at D384 to form a (iv) highly active DISC, subsequently the active catalytic subunits are then (v) autoproteolytically cleaved at D210/216 and released from the DISC to allow for (vi) further cycling and ultimately cell death. (b) Y380 phosphorylation-mediated inhibition of procaspase-8. (i) cytoplasmic procaspase-8 is phosphorylated by Src and later recruited to the CD95/FADD complex leading to (ii) dimerization, procaspase-8 DED chain assembly and binding of an unknown partner to the phosphorylated tyrosine residue leading to steric hindrance and/or a conformational change of the catalytic site. This is followed by (iii) autoproteolytic cleavage at D384 to form a (iv) complex with low enzymatic activity and (v) prevent further autoproteolytic cleavage and release of the p18 subunit therefore blocking (vi) cycling of procaspase-8 at the DISC.