Structure of vaccinia virus A46, an inhibitor of TLR4 signaling pathway, shows the conformation of VIPER motif.
Vaccinia virus (VACV) encodes many proteins that interfere with the host immune system. Vaccinia virus A46 protein specifically targets the BB-loop motif of TIR-domain-containing proteins to disrupt receptor:adaptor (e.g., TLR4:MAL and TLR4:TRAM) interactions of the toll-like receptor signaling. The crystal structure of A46 (75-227) determined at 2.58 Å resolution showed that A46 formed a homodimer and adopted a Bcl-2-like fold similar to other VACV proteins such as A52, B14, and K7. Our structure also revealed that VIPER (viral inhibitory peptide of TLR4) motif resides in the α1-helix and six residues of the VIPER region were exposed to surface for binding to target proteins. In vitro binding assays between wild type and six mutants A46 (75-227) and full-length MAL identified critical residues in the VIPER motif. Computational modeling of the A46:MAL complex structure showed that the VIPER region of A46 and AB loop of MAL protein formed a major binding interface. In summary, A46 is a homodimer with a Bcl-2-like fold and VIPER motif is believed to be involved in the interaction with MAL protein based on our binding assays.
Department of Life Sciences, University of Seoul, Seoul, 130-743, Republic of Korea.
Yongwoon
Y
Kim
Hasup
H
Lee
Lim
L
Heo
Chaok
C
Seok
Jungwoo
J
Choe
D020816:Amino Acid Motifs; D006801:Humans; D008958:Models, Molecular; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics
C413651:A46R protein, vaccinia virus; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D051197:Toll-Like Receptor 4; D014764:Viral Proteins
VIPER motif; innate immunity; toll-like receptor; vaccinia virus