Anthrax toxin receptor 2-dependent lethal toxin killing in vivo.
Anthrax toxin receptors 1 and 2 (ANTXR1 and ANTXR2) have a related integrin-like inserted (I) domain which interacts with a metal cation that is coordinated by residue D683 of the protective antigen (PA) subunit of anthrax toxin. The receptor-bound metal ion and PA residue D683 are critical for ANTXR1-PA binding. Since PA can bind to ANTXR2 with reduced affinity in the absence of metal ions, we reasoned that D683 mutant forms of PA might specifically interact with ANTXR2. We show here that this is the case. The differential ability of ANTXR1 and ANTXR2 to bind D683 mutant PA proteins was mapped to nonconserved receptor residues at the binding interface with PA domain 2. Moreover, a D683K mutant form of PA that bound specifically to human and rat ANTXR2 mediated killing of rats by anthrax lethal toxin, providing strong evidence for the physiological importance of ANTXR2 in anthrax disease pathogenesis.
Scobie
Heather M
HM
Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.
Wigelsworth
Darran J
DJ
Marlett
John M
JM
Thomas
Diane
D
Rainey
G Jonah A
GJ
Lacy
D Borden
DB
Manchester
Marianne
M
Collier
R John
RJ
Young
John A T
JA
D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology / Q000633:toxicity*; D001408:Bacillus anthracis / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000276:immunology / Q000633:toxicity*; D001483:Base Sequence; D006801:Humans; D008136:Longevity / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000276:immunology; D018000:Receptors, Peptide / Q000276:immunology / Q000378:metabolism*
C473287:ANTXR1 protein, human; C447150:ANTXR2 protein, human; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors