1PYO

Crystal Structure of Human Caspase-2 in Complex with Acetyl-Leu-Asp-Glu-Ser-Asp-cho

Summary for 1PYO

• Entry DOI: 10.2210/pdb1pyo/pdb
• Related PRD ID: PRD_000241
• Descriptor: Caspase-2, ACETYL-LEU-ASP-GLU-SER-ASJ, ... (4 entities in total)
• Functional Keywords: apoptosis, caspase, alpha-beta, thiol protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion outer membrane; Multi-pass membrane protein (By similarity): P36114
• Total number of polymer chains: 6
• Total formula weight: 62601.63

Authors

Schweizer, A.,Briand, C.,Grutter, M.G. (deposition date: 2003-07-09, release date: 2003-08-26, Last modification date: 2023-11-15)

Primary citation

Schweizer, A.,Briand, C.,Grutter, M.G.
Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway.
J.Biol.Chem., 278:42441-42447, 2003

PubMed Abstract: 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.

PubMed: 12920126
DOI: 10.1074/jbc.M304895200

Experimental method

X-RAY DIFFRACTION (1.65 Å)