with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position
Reaction: Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position
Other name(s): CPP32; apopain; yama protein
Comments: Caspase-3 is an effector/executioner caspase, as are caspase-6 (EC 3.4.22.59) and caspase-7 (EC 3.4.22.60) [5]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [3,5]. Procaspase-3 can be activated by caspase-1 (EC 3.4.22.36), caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) as well as by the serine protease granzyme B [1]. Caspase-3 can activate procaspase-2 (EC 3.4.22.55) [2]. Activation occurs by inter-domain cleavage followed by removal of the N-terminal prodomain [6]. Although Asp-Glu-(Val/Ile)-Asp is thought to be the preferred cleavage sequence, the enzyme can accommodate different residues at P2 and P3 of the substrate [4]. Like caspase-2, a hydrophobic residue at P5 of caspase-3 leads to more efficient hydrolysis, e.g. (Val/Leu)-Asp-Val-Ala-Asp is a better substrate than Asp-Val-Ala-Asp . This is not the case for caspase-7 [4]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MEROPS, Metacyc, PDB, CAS registry number: 169592-56-7
References:
1. Krebs, J.F., Srinivasan, A., Wong, A.M., Tomaselli, K.J., Fritz, L.C. and Wu, J.C. Heavy membrane-associated caspase 3: identification, isolation, and characterization. Biochemistry 39 (2000) 16056-16063. [PMID: 11123933]
2. Li, H., Bergeron, L., Cryns, V., Pasternack, M.S., Zhu, H., Shi, L., Greenberg, A. and Yuan, J. Activation of caspase-2 in apoptosis. J. Biol. Chem. 272 (1997) 21010-21017. [PMID: 9261102]
3. Nicholson, D. and Thornberry, N.A. Caspase-3 and caspase-7. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1298-1302.
4. Fang, B., Boross, P.I., Tozser, J. and Weber, I.T. Structural and kinetic analysis of caspase-3 reveals role for S5 binding site in substrate recognition. J. Mol. Biol. 360 (2006) 654-666. [PMID: 16781734]
5. Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821-846. [PMID: 11104820]
6. Martin, S.J., Amarante-Mendes, G.P., Shi, L., Chuang, T.H., Casiano, C.A., O'Brien, G.A., Fitzgerald, P., Tan, E.M., Bokoch, G.M., Greenberg, A.H. and Green, D.R. The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism. EMBO J. 15 (1996) 2407-2416. [PMID: 8665848]