Caspases Structure

Eamshaw, W. C., Martins, L. M., and Kaufmann, S. H., 1999, Mammalian caspases structure, activation, substrates, and functions during apoptosis. Anna Rev Biochem 68 383-424. 

Earnshaw, W.C., Martins, L.M. and Kaufmann, S.H. Mammalian Caspases Structure, Activation, Substrates and Functions during Apoptosis (1999) Ann. Rev. Biochem. 68, 383-424. 

Nicholson, D. W., 1999, Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 6, 1028-42. 

Earnshaw WC, Martins LM, Kaufmann SH (1999), Mammalian caspases structure,... 

Caspase-9 phosphorylation by Akt induces a modification in the caspase structure rendering it unable to form the tetramer required for activity. There is also evidence that phosphorylation may regulate caspase-2 activity (Nutt et al., 2005 Shin et al., 2005). 

Earnshaw. W. C, Martins. L. M., and Kaulinatm. 8. IL 19i) j Mammalian caspases Structure, aclivalion. subsiralcs. and luik-tions during apoptosis.. Annu. Kev, /Inidiem. 68 484 424. 

Figure 18.2 Phylogenetic analysis segregates the human caspases into two major subfamilies, one based on caspase-1 previously referred to as ICE, for interleukin-converting enzyme, and the other based on similarities to the C. elegans cell death gene, ced-3. Further classification of the caspases is possible into those that mediate cytokine maturation that are involved in inflammation, those with a short prodomain involved in the effector phase of apoptosis (shown boxed), and those with a long prodomain that are involved in the initiator phase of apoptosis (not boxed). Note evolutionary distances are not accurately represented in this dendrogram. (Adapted from Nicholson, D.W. (1999). Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 6 1028-1042.)...

Death domain (DD) superfamily consists of structurally related homotypic interaction motifs of approximately 90 amino acids. The motifs are organized in six antiparallel amphipathic a-helices, the so-called DD fold. The four members of the super family are the death domain (DD), the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the Pyrin domain. All are important mediators for the assembly of caspase activating complexes. 

Many of the morphological and biochemical changes that occur in cells that die by necrosis are very different from those that occur in apoptosis. During necrosis cells swell, mitochondria and endoplasmic reticulum lose their structure and become dysfunctional and the nuclear membrane becomes disrupted (Fig. 35-1). Necrotic death is independent of premitochondrial apoptotic proteins such as Bax, cytochrome c release and caspase activation. Necrosis is further distinguished from apoptosis by the fact that necrosis usually occurs as the result of a traumatic physical injury or stroke and cells die en masse, whereas apoptosis typically occurs in individual cells within a population of surviving neighbors. 

Crystal structure of gingipain R an Arg-specific bacterial cysteine proteinase with a caspase-like fold. EMBOJ. 1999, 18, 5453-5462. 

We tested this strategy on the enzyme caspase-3, a cysteine-aspartyl protease that is one of the central executioners of apoptosis. Excess apoptosis is attributed to a variety of diseases, from stroke to Alzheimer s Disease to sepsis, making caspase-3 a popular drug target [25]. The enzyme also made an ideal starting point for constructing extenders. It is well characterized both structurally and mechanistically and contains an active site cysteine residue that is irreversibly alkylated by small molecule inhibitors. 

All of these features contrast with the structure of the second extender-fragment complex, shown in Fig. 9.9b. Here, the extender forces itself into the S2 pocket, but the disulfide linker then curves back to place the thiophene sul-fone into the S4 pocket. The sulfone makes some of the same hydrogen bonds as the salicylic acid and the aspartyl residue in the tetrapeptide but with completely different chemistry. The flexibility of caspase-3 to accommodate different... 

Fig. 9.9 (a) Structure of the salicylic acid fragment covalently bound to caspase-3 (gray), superimposed on a tetrapeptide-based inhibitor (green). Note the collapse of the S2 pocket and the widening of the S4 pocket to accommodate the salicylic acid moiety, (b) Structure of a second fragment covalently bound to caspase-3 (blue) superimposed on... 

O Brien, T Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design. J. Med. 

Romanowski, M.J. Structural analysis of caspase-1 inhibitors derived from Tethering. Acta Crystallogr. 2005, F61, 451-458. 

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