Ken Bradley,Ph.D

Office Phone: 310-206-7465
Lab Phone: 310-206-7517
Office: Molecular Sciences Building 2825
Lab: Molecular Sciences Building 2817
Email: kbradley@microbio.ucla.edu

Research Interest:
Anthrax is the disease resulting from infection by spores of the Gram-positive bacterium Bacillus anthracis. Virulence of B. anthracis is associated with two secreted protein toxins, edema toxin and lethal toxin, which are collectively referred to as anthrax toxin. Both of these two toxins are themselves comprised of two separate proteins: a catalytic, or “A” moiety, and a binding, or “B” moiety. In the case of edema toxin, the A moiety, edema factor (EF), is an adenylate cyclase. The A moiety for lethal toxin is lethal factor (LF), a Zn2+-dependent metalloproteinase that cleaves host MAP kinase kinase proteins. Both toxins share a common B moiety, known as protective antigen (PA). PA functions to bind edema toxin and lethal toxin to target cells and transport the catalytic A moieties into the cytosol where they can effect their functions. As such, the interaction between PA and its target cell is crucial for the ability of anthrax toxin to enter host cells, and therefore important for the pathogenesis of B. anthracis.

We originally identified the anthrax toxin receptor (ATR) as a cellular receptor for PA. ATR is a type I transmembrane protein derived from the tumor endothelial marker 8 gene (TEM8). Very little is known about TEM8 other than its transcription is upregulated during the formation of new blood vessels, a process known as angiogenesis. One of the projects in our lab is to determine the natural function(s) of ATR/TEM8.

Recently, in conjunction with Dr. John Young’s laboratory at the University of Wisconsin, a second cellular receptor for anthrax toxin was identified. This second receptor is encoded by the human capillary morphogenesis gene 2 (CMG2), which is also upregulated on endothelial cells during angiogenesis.

One notable feature of ATR and CMG2 is the presence of an extracellular von Willebrand factor A (VWA) domain, also known as an inserted (I) domain. VWA/I domains are structurally conserved domains that function as protein-protein interaction modules and are found in a large number of proteins, including members of the integrin family. We have shown that the PA subunit of anthrax toxin binds directly to the ATR I domain in a manner that appears to mimic the binding of integrins to their natural ligands. We are currently focusing on better defining the toxin-receptor interaction and using this information to develop small molecule inhibitors that block anthrax toxin binding to ATR.

Our understanding of the events that follow translocation of EF and LF into the host cytosol is incomplete. However, we do know that within 90 minutes of LF translocation into mouse macrophages, cell lysis occurs. Furthermore, destruction of lymph nodes is commonly seen in anthrax patients. Therefore, the interaction of toxin with host immune cells seems to play an important role in disease progression. To better understand this interaction, our lab is performing somatic cell genetic screens to elucidate the cellular events that occur after LF enters the cytosol of macrophage cell lines.

Recent Publications:

Heather M. Scobie, G. Jonah A. Rainey, Kenneth A. Bradley *, and John A. T. Young. "Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor". PNAS (2003)
Publication Link

K.A. Bradley, J.A.T. Young (2003) Anthrax toxin receptor proteins. Biochemical Pharmacology 65: 309-314.
Publication Link

K.A. Bradley, J. Mogridge, M. Mourez, R.J. Collier, J.A.T. Young (2001) Identification of the cellular receptor for anthrax toxin. Nature 414: 225-229.
Publication Link