Crystal Structure of a Viral Flip: Insights into Flip-mediated Inhibition of Death Receptor Signaling.
From: Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, New Jersey 08544, USA.
The Journal of biological chemistry
- Publish Date: Feb 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 5
- Pages: 2960-8
- Medium: Print
- Language: English
- Citation (JAMA): Li Feng-Yen, Jeffrey Philip D, Yu Jong W, et al. Crystal Structure of a Viral Flip: Insights into Flip-mediated Inhibition of Death Receptor Signaling.. J. Biol. Chem. Feb 2006;281:2960-8
Abstract
Death receptor signaling is initiated by the assembly of the death-inducing signaling complex, which culminates in the activation of the initiator caspase, either caspase-8 or caspase-10. A family of viral and cellular proteins, known as FLIP, plays an essential role in the regulation of death receptor signaling. Viral FLIP (v-FLIP) and short cellular FLIP (c-FLIPS) inhibit apoptosis by interfering with death receptor signaling. The structure and mechanisms of v-FLIP and c-FLIPS remain largely unknown. Here we report a high resolution crystal structure of MC159, a v-FLIP derived from the molluscum contagiosum virus, which is a member of the human poxvirus family. Unexpectedly, the two tandem death effector domains (DEDs) of MC159 rigidly associate with each other through a hydrophobic interface. Structure-based sequence analysis suggests that this interface is conserved in the tandem DEDs from other v-FLIP, c-FLIPS, and caspase-8 and -10. Strikingly, the overall packing arrangement between the two DEDs of MC159 resembles that between the caspase recruitment domains of Apaf-1 and caspase-9. In addition, each DED of MC159 contains a highly conserved binding motif on the surface, to which loss-of-function mutations in MC159 map. These observations, in conjunction with published evidence, reveal significant insights into the function of v-FLIP and suggest a mechanism by which v-FLIP and c-FLIPS inhibit death receptor signaling.
Mesh Headings (Keywords): Binding Sites, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 10, Caspase 8, Caspases, Conserved Sequence, Crystallography, X-Ray, Intracellular Signaling Peptides and Proteins, Molluscum contagiosum virus, Receptors, Tumor Necrosis Factor, Signal Transduction, Viral Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 16317000
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