First time at Proteopedia? Click on the green links: they change the 3D image. Click and drag the molecules. Proteopedia is a 3D, interactive encyclopedia of proteins, RNA, DNA and other molecules. With a free user account, you can edit pages in Proteopedia. Visit the Main Page to learn more.
Molecular Playground/Caspase-9 Regulation
One of the CBI Molecules being studied in the University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst and on display at the Molecular Playground.
Caspase-9 belongs to a family of "molecular scissors" called cysteine aspartate proteases. These proteases are the facilitators of apoptosis, the highly process of programmed cell death which is an important cellular process critical for normal development and stability of an organism.
Caspase-9 is regulated by controlling its multimeric state through monomer-dimer transitions. Caspase-9 exists as an inactive monomer and becomes active upon dimerization. It is in this dimeric state that caspase-9 can “cut” its intended protein partners (called substrates) at a specific amino acid sequence. X-linked inhibitors of apoptosis proteins, specifically the BIR3 domain, bind to monomeric caspase-9 to block dimerization thus preventing activation.
Caspase-9 in the active, “prepared to cut” state, exists as a dimer. The dimer can be described as two monomers of a large and small subunit related by two-fold symmetry. The dimer is formed through interactions of the amino acids on a β-strand from each monomer which forms a continuous central β –sheet . In addition, a seven residue loop also makes interactions across the interface. A loop bundle exists in this molecule as well and when properly ordered, it is able to “bind and cut” its substrate.
The protein-protein interface of the Caspase-9/XIAP BIR3 complex is dominated by a high level of shape complimentarily, a large collection of van der Walls contacts, and 11 intermolecular hydrogen bonds scattered throughout the entire 2200 Å2 interface of the complex . This interaction prevents caspase-9 from dimerizing as well as prevents the organization of the loop bundle thus making the molecule inactive.
- http://www.pdb.org/pdb/explore/explore.do?structureId=1JXQ Cleaved Caspase-9 Dimer ( PDB ID ; 1JXQ) at RCSB PDB]
- http://www.pdb.org/pdb/explore/explore.do?structureId=1NW9 Caspase-9/XIAP BIR3 Inhibitory Complex ( PDB ID ; 1NW9) at RCSB PDB]
3D structures of caspase
For additional information, see: Cancer
-  Renatus, M.; Stennicke, H. R.; Scott, F. L.; Liddington, R. C.; Salvesen, G. S., Dimer formation drives the activation of the cell death protease caspase 9. PNAS 2001, 98, (25), 14250.
-  Shiozaki, E. N.; Chai, J.; Rigotti, D. J.; Riedl, S. J.; Li, P.; Srinivasula, S. M.; Alnemri, E. S.; Fairman, R.; Shi, Y., Mechanism of XIAP-mediated inhibition of caspase-9. Molecular Cell 2003, 11, (2), 519-527.