Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling.
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.
Li
Feng-Yen
FY
Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, New Jersey 08544, USA.
Jeffrey
Philip D
PD
Yu
Jong W
JW
Shi
Yigong
Y
D001665:Binding Sites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D047908:Intracellular Signaling Peptides and Proteins; D008977:Molluscum contagiosum virus / Q000737:chemistry; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014764:Viral Proteins / Q000737:chemistry*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018124:Receptors, Tumor Necrosis Factor; D014764:Viral Proteins; C509979:viral FLIP protein, Molluscum contagiosum virus; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human