1i4e
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CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX
OverviewOverview
Apoptosis is a highly regulated process that is crucial for normal, development and homeostasis of multicellular organisms. The p35 protein, from baculoviruses effectively prevents apoptosis by its broad-spectrum, caspase inhibition. Here we report the crystal structure of p35 in complex, with human caspase-8 at 3.0 A resolution, and biochemical and mutagenesis, studies based on the structural information. The structure reveals that, the caspase is inhibited in the active site through a covalent thioester, linkage to p35, which we confirmed by gel electrophoresis, hydroxylamine, treatment and mass spectrometry experiments. The p35 protein undergoes, dramatic conformational changes on cleavage by the caspase. The, repositioning of the amino terminus of p35 into the active site of the, caspase eliminates solvent accessibility of the catalytic dyad. This may, be crucial for preventing hydrolysis of the thioester intermediate, which, is supported by the abrogation of inhibitory activity through mutations at, the N terminus of p35. The p35 protein also makes conserved contacts with, the caspase outside the active-site region, providing the molecular basis, for the broad-spectrum inhibitory activity of this protein. We demonstrate, a new molecular mechanism of caspase inhibition, as well as protease, inhibition in general.
DiseaseDisease
Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[601763], Breast cancer, protection against OMIM:[601763], Hepatocellular carcinoma, somatic OMIM:[601763]
About this StructureAbout this Structure
1I4E is a Protein complex structure of sequences from Escherichia coli. Full crystallographic information is available from OCA.
ReferenceReference
Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex., Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H, Nature. 2001 Mar 22;410(6827):494-7. PMID:11260720
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