Long range communication in the envelope protein domain III and its effect on the resistance of West Nile virus to antibody-mediated neutralization.
The envelope protein domain III (ED3) of West Nile virus is the major virus-specific neutralization domain and harbors most of the critical mutations that induce resistance against antibody-mediated neutralization. We investigated the molecular mechanisms of neutralization resistance by studying the biophysical perturbations of monoclonal antibody (mAb)-resistant mutations on ED3 wild type. Our results showed that although the solution structure between ED3 wild type and mutants was preserved, the mutations that confer the highest degree of resistance to mAbs showed low protein stability and high local dynamic motions. Interestingly, the latter was observed in regions outside the mutation sites, indicating long range communications within ED3. Thus, we hypothesized that the mechanisms involved in resistance to mAb neutralization may include, in addition to mutations in the epitope, long range effects among distant structural elements. This hypothesis is consistent with reported mutations in other flaviviruses whose surfaces are not exposed for the interaction with other macromolecules, yet they confer mAb neutralization resistance.
Maillard
Rodrigo A
RA
Department of Biochemistry and Molecular Biology, Galveston, Texas 77555-1055.
Jordan
Matthew
M
Department of Biochemistry and Molecular Biology, Galveston, Texas 77555-1055.
Beasley
David W C
DWC
Department of Microbiology and Immunology, Galveston, Texas 77555-1055; Department of Sealy Center for Vaccine Development, Galveston, Texas 77555-1055; Institute for Human Infections and Immunity, the University of Texas Medical Branch, Galveston, Texas 77555-1055.
Barrett
Alan D T
ADT
Department of Sealy Center for Vaccine Development, Galveston, Texas 77555-1055; Institute for Human Infections and Immunity, the University of Texas Medical Branch, Galveston, Texas 77555-1055; Department of Pathology, Galveston, Texas 77555-1055.
Lee
J Ching
JC
Department of Biochemistry and Molecular Biology, Galveston, Texas 77555-1055. Electronic address: jclee@utmb.edu.
D000911:Antibodies, Monoclonal / Q000276:immunology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009500:Neutralization Tests; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D014902:West Nile virus / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D014759:Viral Envelope Proteins