Contact Information:

Dept. of Microbiology and
Molecular Genetics

Harvard Medical School

200 Longwood Ave.

Boston, MA 02115

phone: 617-432-1930

fax: 617-432-0115

jcollier@hms.harvard.edu

Research Summary

The symptoms of many bacterial diseases are due largely to the actions of toxic proteins released by the bacteria. Diphtheria, anthrax, cholera, and tetanus toxins are well-known examples. We study these proteins primarily to understand the biochemical basis of bacterial disease and to gain insight into how proteins insert into and cross membranes.

The most potent bacterial toxins act by penetrating into mammalian cells and covalently modifying target substrates within the cytosol. We are currently focusing on diphtheria and anthrax toxins, applying genetic, biochemical, and biophysical methods to generate detailed models of each step in toxin action. How these structurally unrelated toxins insert into bilayers under the influence of low endosomal pH and translocate their enzymic moieties to the cytosol represents a problem of major interest.

Knowledge of the structures and actions of toxins has served as the basis for developing novel pharmaceuticals. We have recently devised new approaches to treating anthrax based on knowledge of how the three components of anthrax toxin assemble into toxic complexes at the mammalian cell surface and how they function during translocation across the endosomal membrane.

Selected Publications

Lacy DB, Mourez M, Fouassier A, Collier RJ. Mapping the anthrax protective antigen binding site on the lethal and edema factors. J Biol Chem. 2001 Nov 19;277:3006-3010

Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C, Bienkowska J, Lacy DB, Collier RJ, Park S, Leppla SH, Hanna P, Liddington RC. Crystal structure of the anthrax lethal factor. Nature. 2001 Nov 8;414(6860):229-33.

Bradley KA, Mogridge J, Mourez M, Collier RJ, Young JA. Identification of the cellular receptor for anthrax toxin. Nature. 2001 Nov 8;414(6860):225-9.

Mourez M, Kane RS, Mogridge J, Metallo S, Deschatelets P, Sellman BR, Whitesides GM, Collier RJ. Designing a polyvalent inhibitor of anthrax toxin. Nat Biotechnol. 2001 Oct;19(10):958-61.

Sellman BR, Mourez M, Collier RJ. Dominant-negative mutants of a toxin subunit: an approach to therapy of anthrax. Science. 2001 Apr 27;292(5517):695-7.