Both dimerization and interdomain processing are essential for caspase-4 activation.
A subgroup of caspase family of inflammatory caspases (-1, -4, -5, -11, and -12) play important role during cytokine maturation and inflammation but their regulation is not well understood as much as the initiator and effector caspases. Here, the biochemical mechanism of caspase-4 activation is elucidated. With citrate, a well-known kosmotrope to enhance the monomer-dimer transition, caspase-4 was activated approximately 40 times that was comparable with that of caspase-9 ( approximately 75-fold increments). The activation reaction was mainly bimolecular (n=1.67+/-0.04) for monomeric caspase-4. In addition, the interdomain cleavage was also responsible to activate caspase-4 more than 100-fold, again comparable with that of effector caspases where the proteolytic processing is considered as the sole activation mechanism. Thus, caspase-4 shows a novel activation mechanism of the synergism between dimerization and proteolysis that sharply differs from the established activation mechanism of dimerization for initiators and interdomain cleavage for effector caspases.
Karki
Pratap
P
Research Center for Proteineous Materials (RCPM) and Department of Bio-Materials Engineering, School of Medicine, Chosun University, Gwangju 501-759, Republic of Korea.
Dahal
Giri Raj
GR
Park
Il-Seon
IS
D001665:Binding Sites; D053471:Caspases, Initiator / Q000737:chemistry*; D019343:Citric Acid / Q000737:chemistry*; D003198:Computer Simulation; D019281:Dimerization; D004789:Enzyme Activation; D008956:Models, Chemical; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D019343:Citric Acid; C093516:CASP4 protein, human; D053471:Caspases, Initiator