Caspase Related Peptides Products

Definition

Caspases are a family of aspartate specific cysteine proteases that play an important role in apoptosis, necrosis and inflammation¹.

Discovery

Caspases were first identified in the nematode C. elegans. It was found that the gene ced-3 was required for cell death during C.elegans development². In 1993, the protein encoded by the ced-3 gene was identified as a cysteine protease and it was found that it had similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1) which at the time was the only known caspase³. Other mammalian caspases were subsequently identified.

Classification

There are three types of apoptotic caspases: initiator, effector and inflammatory caspases. Initiator caspases (e.g. CASP2, CASP8, CASP9 and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them⁴. Effector caspases (e.g. CASP3, CASP6 and CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process⁴. Inflammatory caspases are involved in immune response (e.g. CASP1, CASP4, CASP5, CASP11, CASP12 and CASP13). Caspase inhibitors regulate the initiation of this cascade⁴.

Structural Characteristics

Caspases are synthesized as inactive zymogens or procaspases.  Activation of caspases occurs by cleavage of the prodomain in the procaspases⁵.  The caspase catalytic domain is composed of a twisted, mostly parallel ß-sheet sandwiched between two layers of a-helices. Also they contain an active cysteine residue in their catalytic domain⁵.  In addition to the catalytic domain, both inflammatory and initiator caspases carry at their N-termini, one or two copies of CARD or DED modules, which are critical for their activation in vivo. These modules are mainly composed of six antiparallel a-helices, with helices a1–a5 building an a-helical Greek key⁵. The general structure of a caspase inhibitor is [tetrapeptide]-CO-CH2-X, that binds to the Cys²⁸⁵ in the active site of caspases⁵.

Mode of action

Caspases cleave the substrate after an Asp residue6.  There are several hundred substrates for caspases.  Initially activation of initiator caspases occurs as a result of an extrinsic or intrinsic death signal⁶.  Activated initiator caspases cleave effector caspases that in turn cleave the substrate at an Asp residue⁶.  For example, caspase-8 cleaves the pro-apoptotic protein Bid that gets activated and translocates into the mitochondria where it activates other pro-apoptotic proteins, Bax and Bak thus amplifying the death signal⁶.

Functions

Caspases such as caspase-1 are involved in the activation of pro-inflammatory cytokines such as Interleukin 1 and interleukin 18^5,6.  Caspases play an important role in apoptosis. One of the hallmark feature of apoptotic cell death is genomic disassembly and proteolysis^5,6.   By cleaving their substartes, caspases inactivate cell cycle progression and DNA repair processes.  They also activate several pro-apoptotic proteins^5,6.  In some cases Caspases’ role in aberrant processing events has shown their involvement in neurodegenerative disorders such as Huntington disease and Alzheimer’s disease⁶.  Some of the final targets of caspases include: nuclear lamins, ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45), PARP (poly-ADP ribose polymerase) and PAK2 (P 21-activated kinase 2)⁶.  Caspases are also implicated in embryonic development and T and B cell differentiation⁷.