Format

Send to

Choose Destination
See comment in PubMed Commons below
J Biol Chem. 2013 Mar 29;288(13):9058-65. doi: 10.1074/jbc.M113.452110. Epub 2013 Feb 7.

Engineering anthrax toxin variants that exclusively form octamers and their application to targeting tumors.

Author information

1
Laboratory of Parasitic Diseases, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract

Anthrax toxin protective antigen (PA) delivers its effector proteins into the host cell cytosol through formation of an oligomeric pore, which can assume heptameric or octameric states. By screening a highly directed library of PA mutants, we identified variants that complement each other to exclusively form octamers. These PA variants were individually nontoxic and demonstrated toxicity only when combined with their complementary partner. We then engineered requirements for activation by matrix metalloproteases and urokinase plasminogen activator into two of these variants. The resulting therapeutic toxin specifically targeted cells expressing both tumor associated proteases and completely stopped tumor growth in mice when used at a dose far below that which caused toxicity. This scheme for obtaining intercomplementing subunits can be employed with other oligomeric proteins and potentially has wide application.

PMID:
23393143
PMCID:
PMC3610978
DOI:
10.1074/jbc.M113.452110
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center