4ee2
From Proteopedia
Crystal Structure of Anthrax Protective Antigen K446M Mutant to 1.91-A Resolution
Structural highlights
Function[PAG_BACAN] One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. PA binds to a receptor (ATR) in sensitive eukaryotic cells, thereby facilitating the translocation of the enzymatic toxin components, edema factor and lethal factor, across the target cell membrane. PA associated with LF causes death when injected, PA associated with EF produces edema. PA induces immunity to infection with anthrax. Publication Abstract from PubMedMany toxins assemble into oligomers on the surface of cells. Local chemical cues signal and trigger critical rearrangements of the oligomer, inducing the formation of a membrane-fused or channel state. Bacillus anthracis secretes two virulence factors: a tripartite toxin and a poly-gamma-d-glutamic acid capsule (gamma-DPGA). The toxin's channel-forming component, protective antigen (PA), oligomerizes to create a prechannel that forms toxic complexes upon binding the two other enzyme components, lethal factor (LF) and edema factor (EF). Following endocytosis into host cells, acidic pH signals the prechannel to form the channel state, which translocates LF and EF into the host cytosol. We report gamma-DPGA binds to PA, LF, and EF, exhibiting nanomolar avidity for the PA prechannel oligomer. We show PA channel formation requires the pH-dependent disruption of the intra-PA domain-2-domain-4 (D2-D4) interface. gamma-DPGA stabilizes the D2-D4 interface, preventing channel formation both in model membranes and cultured mammalian cells. A 1.9-A resolution X-ray crystal structure of a D2-D4-interface mutant and corresponding functional studies reveal how stability at the intra-PA interface governs channel formation. We also pinpoint the kinetic pH trigger for channel formation to a residue within PA's membrane-insertion loop at the inter-PA D2-D4 interface. Thus, gamma-DPGA may function as a chemical cue, signaling that the local environment is appropriate for toxin assembly but inappropriate for channel formation. Anthrax toxin protective antigen integrates poly-gamma-D-glutamate and pH signals to sense the optimal environment for channel formation.,Kintzer AF, Tang II, Schawel AK, Brown MJ, Krantz BA Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18378-83. doi:, 10.1073/pnas.1208280109. Epub 2012 Oct 24. PMID:23100533[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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