CASP9

CASP9 Background

Caspase-9, encoded by the CASP9 gene, is one of the initiator caspases ^[1] that belong to cysteine protease family. Caspase-9 is expressed early in embryogenesis and ubiquitously in adult tissues. Human caspase-9 contains three major domains: a prodomain with a caspase recruitment domain (CARD), the large subunit catalytic domain (LSCD), and the small subunit catalytic domain (SSCD) ^[2]. Both LSCD and SSCD are also called catalytic domain. Prodomain and catalytic domains are connected by the linker domain, which contains the sites of amino acid residues involved in the proteolytic processing and post-translational modifications of the procaspase-9 ^[2]. All caspases are synthesized as inactive zymogens in cells and must undergo proteolytic cleavages to become fully activated. The activation of caspase-9 is complexed with apoptotic protease activating factor 1 (APAF-1) by their respective CARD domain ^[3]. Yini Li et al. demonstrated that the APAF-1 apoptosome activates caspase-9 by either suppressing the inhibition mediated by the CARD domain or stimulating the catalytic activity of the protease domain ^[4]. Active caspase-9 further stimulates downstream effector caspase and some Bcl2 family members, thus leading to apoptosis ^[5][6]. The cleavage of procaspase-9 is blocked by ERK1/2, DYRK1A, CDK1-cylinB1, and p38α at the Thr125 phosphorylation site, which is a well-known inhibitory site of caspase-9. Mutation of Caspase- 9 results in embryonic lethality and defective brain development associated with decreased apoptosis ^[7].

[1] Boatright KM, Salvesen GS Mechanisms of caspase activation [J]. Curr Opin Cell Biol. 2003 Dec; 15(6):725-31.
[2] Yuan S, et al. Structure of an apoptosome-procaspase-9 CARD complex [J]. Structure, 2010, 18(5):571-583.
[3] Li P, Nijhawan D, et al. Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade [J]. Cell. 1997; 91 (b): 479-489.
[4] Yini Li, Mengying Zhou, et al. Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme [J]. PNAS February 14, 2017, 114 (7) 1542-1547.
[5] Cohen G.M Caspases the executioners of apoptosis [J]. Biochem. J. 1997; 326: 1-16.
[6] Clem R.J, Cheng E.H, et al. Modulation of cell death by Bcl-XL through caspase interaction [J]. Proc. Natl. Acad. Sci. USA. 1998; 95: 554-559.
[7] Razqallah Hakem, Anne Hakem, et al. Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo [J]. VOLUME 94, ISSUE 3, P339-352, AUGUST 07, 1998.