Cofactors of Caspase Activation

Activation of the caspases requires the help of a number of cofactors that are also known as activators or adaptors. Different cofactors are involved depending on the trigger mechanism of caspase activation. A central function of the cofactors is to bring about aggregation and thus activation of the procaspases. This occurs by specific protein-protein interactions with the help of common structural motives. Examples of such motives are the death domains (DD), death effector domains (DED) and the caspase recruitment domains (CARD), which all have a similar structure of six a-heh-ces. 

In the case of the death receptor Fas (see 15.4), activation of the caspase involves a protein that interacts with the cytoplasmic part of the receptor and is known as FADD protein (Fas-associated death domain). The FADD protein has distinct structural motives that mediate specific interactions with other proteins. It interacts via the death domain with the receptor and via the death effector domain with the corresponding caspase (here caspase 8). 

The Apafl protein has been identified as a central cofactor in cytotoxically-triggered apoptosis. The Apafl protein is homologous to Ced4 protein of C. elegans. It binds to the initiator caspase with the help of a CARD motif A CARD motif is found in the Apafl protein and in various caspases (caspases 1, 2, 4, 5 and 9). 

A further cofactor in activation in this system is cytochrome c. The ATP-dependent activation occins in a complex of caspase, Apafl protein and Cyt c, which is also known as the apoptosome. 

---