细胞生物学：chap15细胞衰老与死亡.pptVIP

* * * * * * ? * Caspases (cysteine aspartic acid-specific proteases) are highly specific proteases that cleave their substrates after specific tetrapeptide motifs (P4-P3-P2-P1) where P1 is an Asp residue. The caspase family can be subdivided into initiators, which are able to auto-activate and initiate the proteolytic processing of other caspases, and effectors, which are activated by other caspase molecules. The effector caspases cleave the vast majority of substrates during apoptosis. All caspases have a similar domain structure comprising a pro-peptide followed by a large and a small subunit (see figure). The pro-peptide can be of variable length and, in the case of initiator caspases, can be used to recruit the enzyme to activation scaffolds such as the APAF1 apoptosome. Two distinct, but structurally related, pro-peptides have been identified; the caspase recruitment domain (CARD) and the death effector domain (DED), and these domains typically facilitate interaction with proteins that contain the same motifs. Caspase activation is usually initiated through proteolytic processing of the caspase between the large and small subunits to form a heterodimer. This processing event rearranges the caspase active site into the active conformation. Caspases typically function as heterotetramers, which are formed through dimerization of two caspase heterodimers. Initiator caspases exist as monomers in healthy cells, whereas effector caspases are present as pre-formed dimers. Not all mammalian caspases participate in apoptosis. For example, caspase-1, caspase-4, caspase-5 and caspase-12 are activated during innate immune responses and are involved in the regulation of inflammatory cytokine processing (for example, IL1 and IL18). Interestingly, caspase-12 is expressed as a truncated, catalytically inactive protein in most humans (caspase-12S*). However, a subset of individuals of African descent express full-length caspase-12 (caspase-12L*) and these individuals appear to