Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway.
The cell death protease caspase-2 has recently been recognized as the most apical caspase in the apoptotic cascade ignited during cell stress signaling. Cytotoxic stress, such as that caused by cancer therapies, leads to activation of caspase-2, which acts as a direct effector of the mitochondrion-dependent apoptotic pathway resulting in programmed cell death. Here we report the x-ray structure of caspase-2 in complex with the inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-A resolution. Compared with other caspases, significant structural differences prevail in the active site region and the dimer interface. The structure reveals the hydrophobic properties of the S5 specificity pocket, which is unique to caspase-2, and provides the details of the inhibitor-protein interactions in subsites S1-S4. These features form the basis of caspase-2 specificity and allow the design of caspase-2-directed ligands for medical and analytical use. Another unique feature of caspase-2 is a disulfide bridge at the dimer interface, which covalently links the two monomers. Consistent with this finding, caspase-2 exists as a (p19/p12)2 dimer in solution, even in the absence of substrates or inhibitors. The intersubunit disulfide bridge stabilizes the dimeric form of caspase-2, whereas all other long prodomain caspases exist as monomers in solution, and dimer formation is driven by ligand binding. Therefore, the central disulfide bridge appears to represent a novel way of dimer stabilization in caspases.
Schweizer
Andreas
A
Department of Biochemistry, University of Zurich, 8057-Zurich, Switzerland.
Briand
Christophe
C
Grutter
Markus G
MG
D017209:Apoptosis; D001665:Binding Sites; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation
D061945:Caspase Inhibitors; D004220:Disulfides; D004791:Enzyme Inhibitors; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases