Anthrax protective antigen is a calcium-dependent serine protease

Abstract

Bacillus anthracis secretes a three component exotoxin-complex, which contributes to anthrax pathogenesis. Formation of this complex starts with the binding of protective antigen (PA) to its cellular receptor. In this study, we report that PA is a calcium-dependent serine protease and that the protein potentially uses this proteolytic activity for receptor binding. Additionally our findings shed new light on previous research describing the inhibition of anthrax toxins and exotoxin formation. Importantly, inhibition of the proteolytic activity of protective antigen could be a novel therapeutic strategy in fighting B. anthracis-related infections.

Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assembly

“…HD1 occurs in both Sym CDTb and Asym CDTb and features 2 proximal Ca 2+ binding sites ( Fig. 6A) that are highly conserved in this toxin family (54,55). The presence of Ca 2+ was confirmed here for active CDTb using inductively coupled plasma mass spectrometry.…”

The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile

“…Notably, Ca 2+ -coordinating sites were discovered for the HD1 domains residing in both Asym CDTb and Sym CDTb [ 20 ], and analogous calcium ion binding sites were recognized prevously in the HD1 domains of anthrax toxin, iota toxin, as well as being highly conserved throughout this toxin family [ 40 , 41 ]. For anthrax, the role of calcium ions was found to be necessary for both the structural stability and proteolytic activity of the anthrax toxin [ 40 , 42 , 43 ]. In addition to structural calcium ions, extracellular calcium levels are also deemed essential for endocytosis during the intoxication pathway, as calcium depletion was shown effective for protection against anthrax toxin cell penetration [ 44 ].…”

Accurate and selective quantification of anthrax protective antigen in plasma by immunocapture and isotope dilution mass spectrometry

“…Recently, it has been reported that PA83 has calciumdependent protease activity. 12 The PA63 self-associates into a heptamer 6 or an octamer, 13 which can then bind 3 or 4 molecules of LF and/or EF, thus forming LTx, ETx and possibly mixed toxin complexes. The PA63 oligomers form pores on the endosome membranes through which LF and EF are transported into the cytosol, where their combined enzyme activities exert potent synergistic toxic effects.…”