Introduction / Overview of Anthrax Toxin

The third and final protein of anthrax toxin, edema factor (EF) has been recently crystallized. EF is one of the three proteins that comprise anthrax toxin.  The oher two are: protective antigen and lethal factor.  Bacillus anthracis is the bacteria responsible for anthrax.  It has two pieces of extrachromosomal DNA called pXO1 and pXO2 that are responsible for the toxin properties of the bacterium.  pXO2 encodes a protective lipopolysaccharide coat that protects the toxin.  pXO1 is responsible for the genes encoding anthrax toxin.  [1]

Figure 1.  Bacillus anthracis and edema factor with and without calmodulin bound (inset)[1]

Protective antigen is a heptamer composed of identical subunits and a molecular weight of 83 kilodaltons.  It's function is to transport lethal factor and edema factor into the cytosol. The sequence of events are as follows: domain 4 binds to a host cell receptor, furin cleaves the protective antigen releasing a 20 kilodalton fragment (part of domain 1, PA₂₀), the rest of the subunit (PA₆₃) combines with other PA₆₃ and they form a heptamer that creates a pore for protective antigen and lethal factor to go through into the cystosol. [2]

Figure2.  Protective antigen forming a heptamer [2]

Lethal factor is a metalloprotease and inhibits the mitogen-activated protein kinase(MAPK) signal transduction pathway.[3]  It also has four domains.  Domain I binds to PA.  Domain II is similar to Bacillus cereus with its ADP-ribosylating toxin.  Domain III is inside domain II and seems to be a replication of some elements of domain III.  Domain IV is the catalytic domain with its metalloprotease function. [4]

Figure 3. Lethal factor bound to MAPKK-2 [3]

Edema factor is an adenylyl cyclase.  It works by first binding a protein called calmodulin and then ATP.  It then cyclizes ATP to form cAMP.  What is most important about the crystallization of this factor is that it is the first adenylyl cyclase of Class II adenylyl cyclases to be crystalized.  Also striking, the mechanism for cyclase is different from any other known adenylyl cyclase. [5]

Figure 4. EF with and without calmodulin bound.[5]