Crystallization and low-resolution structure of an effector-caspase/P35 complex: similarities and differences to an initiator-caspase/P35 complex.
The aspartate-specific caspases play a pivotal role in the execution of programmed cell death and therefore constitute important targets for the control of apoptosis. Upon ectopic expression, baculovirus P35 inhibits apoptosis in phylogenetically diverse organisms by suppressing the proteolytic activity of the cellular caspases in a cleavage-dependent mechanism. After cleavage by caspase, the P35 fragments remain bound to the target caspase, forming an inhibitory complex that sequesters the caspase from further activity. Crystals of a complex between P35 and Sf-caspase-1, an insect effector-caspase, were grown. A 5.2 A resolution structure of this inhibitory complex was determined by molecular-replacement methods. The structure reveals few regions of interaction between the two proteins, much like that observed in the structure of the recently solved human initiator-caspase/P35 complex. In the effector-caspase/P35 complex structure presented here, the P35 molecule shifts towards a loop that is conserved in effector caspases but absent in initiator caspase. This shift could strengthen interactions between the two proteins and may explain the preference of P35 for inhibiting effector-caspases.
Eddins
Michael J
MJ
Department of Chemistry, University of California, Davis, CA 95616, USA.
Lemongello
Donna
D
Friesen
Paul D
PD
Fisher
Andrew J
AJ
D000818:Animals; D020170:Caspase 1 / Q000737:chemistry* / Q000378:metabolism*; D003460:Crystallization; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008958:Models, Molecular; D011487:Protein Conformation; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D020170:Caspase 1