Binding of Anthrax Toxin to Its Receptor Is Similar to α Integrin-Ligand Interactions

The secreted protein toxin produced by Bacillus anthracis contributes to virulence of this pathogen and can cause many of the symptoms seen during an anthrax infection, including shock and sudden death. The cellbinding component of anthrax toxin, protective antigen, mediates entry of the toxin into cells by first binding directly to the extracellular integrin-like inserted (I) domain of the cellular anthrax toxin receptor, ATR. Here we report that this interaction requires an intact metal ion-dependent adhesion site (MIDAS) in the receptor as well as the presence of specific divalent cations. Also, we demonstrate that the toxin-receptor interaction is critically dependent on the Asp-683 carboxylate group of protective antigen, which projects from the receptor binding surface. We propose that this carboxylate group completes the coordination of the MIDAS metal of ATR, mimicking integrin-ligand interactions. The secreted protein toxin produced by Bacillus anthracis contributes to virulence of this pathogen and can cause many of the symptoms seen during an anthrax infection, including shock and sudden death. The cellbinding component of anthrax toxin, protective antigen, mediates entry of the toxin into cells by first binding directly to the extracellular integrin-like inserted (I) domain of the cellular anthrax toxin receptor, ATR. Here we report that this interaction requires an intact metal ion-dependent adhesion site (MIDAS) in the receptor as well as the presence of specific divalent cations. Also, we demonstrate that the toxin-receptor interaction is critically dependent on the Asp-683 carboxylate group of protective antigen, which projects from the receptor binding surface. We propose that this carboxylate group completes the coordination of the MIDAS metal of ATR, mimicking integrin-ligand interactions. Bacillus anthracis, the causative agent of anthrax, is a Gram-positive, spore-forming bacterium that expresses two major virulence factors, a poly-d-glutamate capsule and anthrax toxin. Anthrax toxin is comprises three secreted proteins: a receptor-binding moiety, protective antigen (PA), 1The abbreviations used are: PAprotective antigenELISAenzymelinked immunosorbent assayGFPgreen fluorescent proteinEGFPenhanced green fluorescent proteinATRanthrax toxin receptorMIDASmetal ion-dependent adhesion siteTBSTris-buffered salineCHOChinese hamster ovaryEFedema factorLFlethal factorLFN-DTAamino terminus of LF fused to the catalytic domain of diphtheria toxinD4domain 4VWAvon Willebrand factor type A domain.1The abbreviations used are: PAprotective antigenELISAenzymelinked immunosorbent assayGFPgreen fluorescent proteinEGFPenhanced green fluorescent proteinATRanthrax toxin receptorMIDASmetal ion-dependent adhesion siteTBSTris-buffered salineCHOChinese hamster ovaryEFedema factorLFlethal factorLFN-DTAamino terminus of LF fused to the catalytic domain of diphtheria toxinD4domain 4VWAvon Willebrand factor type A domain. and two catalytic moieties, edema factor (EF) and lethal factor (LF). EF is an adenylate cyclase that disrupts water homeostasis and impairs immune function in the host (1.Leppla S.H. Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 3162-3166Crossref PubMed Scopus (756) Google Scholar, 2.O'Brien J. Friedlander A. Dreier T. Ezzell J. Leppla S. Infect. Immun. 1985; 47: 306-310Crossref PubMed Google Scholar). LF is a Zn2+-dependent metalloproteinase that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family of protein kinases and disrupts signal transduction pathways (3.Duesbery N.S. Webb C.P. Leppla S.H. Gordon V.M. Klimpel K.R. Copeland T.D. Ahn N.G. Oskarsson M.K. Fukasawa K. Paull K.D. Vande Woude G.F. Science. 1998; 280: 734-737Crossref PubMed Scopus (884) Google Scholar, 4.Pellizzari R. Guidi-Rontani C. Vitale G. Mock M. Montecucco C. FEBS Lett. 1999; 462: 199-204Crossref PubMed Scopus (254) Google Scholar, 5.Vitale G. Pellizzari R. Recchi C. Napolitani G. Mock M. Montecucco C. Biochem. Biophys. Res. Commun. 1998; 248: 706-711Crossref PubMed Scopus (361) Google Scholar, 6.Park J.M. Greten F.R. Li Z.W. Karin M. Science. 2002; 297: 2048-2051Crossref PubMed Scopus (419) Google Scholar). PA binds EF and LF to target cells and transports these catalytic subunits into the host cell cytosol where they carry out their enzymatic functions. A cellular receptor that binds PA as anthrax toxin receptor a protein by the J. M. PubMed Scopus Google Scholar). a cellular receptor PA as the protein Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). PA binds directly to the extracellular integrin-like inserted (I) in and J. M. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the binding of PA to the domain is dependent on the presence of divalent as to this interaction J. M. PubMed Scopus Google of the and these major in the a MIDAS by the is which to binding coordination of a divalent metal R. PubMed Scopus Google Scholar, M. J. Biophys. 2002; PubMed Scopus Google Scholar). domain directly the the metal these integrin-ligand M. J. Biophys. 2002; PubMed Scopus Google Scholar). The domain a MIDAS that we a in the binding of this we in the MIDAS of ATR, a carboxylate group in and specific divalent that that anthrax toxin binds in a that is to the binding and their and of to to the and into the J. M. PubMed Scopus Google and and their and by of the by into the and of by of the of to and this the and of The and of this to the and and their The into cells cells and from the by a and and by and to on the of the the type and to a site and a protein of that the of the of type and in protein by to of and and by and to by on and a by to and and their used to and The PA in these and type and PA in and as J. S. 1998; PubMed Scopus Google of type and of into cells transduction by cells of of protein from and of ATR, J. M. PubMed Scopus Google Scholar). by to cell in the presence of by binding of in to well of a in a of in the presence of of in as a of a the by a cells their to PA binding in a the of and a to J. M. PubMed Scopus Google Scholar). The of protein by and the of PA binding by by of on and to in the presence of and The as well as of on and of cells of on The and cells three in and in and and an of protein from to The in and by by an and an in a of and cells on a cell the cell the by The in and the the MIDAS in the of the MIDAS in PA we first used an to the specific metal in the toxin-receptor The of a PA by an of the domain in the presence of divalent cations. of PA to by binding the integrin-ligand M. J. Biophys. 2002; PubMed Scopus Google Scholar, A. Biophys. PubMed Scopus Google to toxin-receptor binding binding dependent on the of toxin binding toxin binding from to directly the of the MIDAS in toxin the first of this an to to metal coordination and binding in M. PubMed Scopus Google Scholar, T. J. PubMed Google Scholar, T. R. J. PubMed Scopus Google Scholar, C.P. M. T. J. PubMed Scopus Google Scholar). The into and this to binding to PA in an of the cause of the as by can that in their M. T. A. R. A. J. PubMed Scopus Google Scholar). The MIDAS a to the metal in the in the the is to metal coordination and of the MIDAS in is to the domain into a that an PubMed Scopus Google Scholar, R. J. 1998; PubMed Scopus Google Scholar). a the MIDAS in PA the into the protein disrupts toxin-receptor interaction as by the of the protein a to type that this cause the of of to as a on the and into an green fluorescent protein and the in hamster cells that anthrax toxin J. M. PubMed Scopus Google Scholar). The cell their to toxin binding in a type cells PA and a the of receptor and the of PA cells to PA cells an to PA binding in this that an intact MIDAS is toxin that of on the cell the that the toxin binding to cells A. PubMed Scopus Google Scholar, A. PubMed Scopus Google intact MIDAS is toxin receptor cells of PA by and an The of protein by and the of PA binding by the cell a and by and an cells and cells type of and an of PA in the cell and the of cells that we the and the of to cells type MIDAS of their to a anthrax toxin PA and the terminus of LF fused to the catalytic domain of diphtheria toxin J. M. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). cells type by this toxin, cells to toxin and cells to toxin type that of the MIDAS toxin receptor a of receptor as seen cell binding and A and this a in PA a divalent and the MIDAS in toxin we PA contributes to the interaction that to the of that to binding by the coordination of the MIDAS metal by of their carboxylate R. PubMed Scopus Google Scholar, M. T. A. R. A. J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J.M. PubMed Scopus Google Scholar). PA a domain we the of PA and that to binding C. Klimpel K.R. Leppla S.H. PubMed Scopus Google Scholar). in the receptor-binding domain and to the to and to PA in and to function in a cell three as a to in cell of the type and the PA that this PA is Asp-683 as a PA of PA domain carboxylate in carboxylate on the as which to in binding J. M. PubMed Scopus Google Scholar, M. Leppla S.H. J. PubMed Google Scholar, M. A. J.M. Leppla S.H. 1998; PubMed Google Scholar). R. M. K. J. Scopus Google in PA is receptor cells to and of type PA to and protein by by an A that of protein in the toxin function the of receptor we this into a receptor-binding domain of PA J. M. PubMed Scopus Google and the of this protein to in a to to a Asp-683 in receptor anthrax in is an to and the the receptor binding domain of PA S. J. Infect. Immun. 2002; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of to anthrax PubMed Scopus Google Scholar, S. Infect. Immun. 2002; PubMed Scopus Google Scholar, Friedlander Infect. Immun. PubMed Google Scholar). to binding of PA to cellular to of anthrax of by a of PA cellular The of this to of anthrax by the of the binds directly to the extracellular of ATR, which an integrin-like inserted as a Willebrand factor type A domain that of and function as interaction 2002; PubMed Scopus Google Scholar). in in and an in to extracellular 2002; PubMed Scopus Google Scholar). extracellular domain and and the in these directly to cell adhesion and extracellular 2002; PubMed Scopus Google Scholar, Sci. 1998; PubMed Scopus Google Scholar). the function of is is that the domain as a interaction the function of which is to on an intact The an intact MIDAS toxin binding that PA binding to PA binding is by the an in a is a of domain Asp-683 is in an in which in receptor binding C. Klimpel K.R. Leppla S.H. PubMed Scopus Google Scholar, M. S. Leppla S.H. Infect. Immun. 1999; PubMed Google Scholar). we and J. M. PubMed Scopus Google Scholar, M. S. Leppla S.H. Infect. Immun. 1999; PubMed Google as the of this M. Leppla S.H. J. PubMed Google that Asp-683 in PA in a in which is a of PA binding to cell that Asp-683 two and that Asp-683 is the into of to their requires divalent an intact and the presence of a in a in the the toxin-receptor binding on the an intact MIDAS in ATR, and the an in an in PA we propose that PA is mimicking a domain and that the receptor binding function of Asp-683 coordination of the metal in ATR. Bacillus anthracis, the causative agent of anthrax, is a Gram-positive, spore-forming bacterium that expresses two major virulence factors, a poly-d-glutamate capsule and anthrax toxin. Anthrax toxin is comprises three secreted proteins: a receptor-binding moiety, protective antigen (PA), 1The abbreviations used are: PAprotective antigenELISAenzymelinked immunosorbent assayGFPgreen fluorescent proteinEGFPenhanced green fluorescent proteinATRanthrax toxin receptorMIDASmetal ion-dependent adhesion siteTBSTris-buffered salineCHOChinese hamster ovaryEFedema factorLFlethal factorLFN-DTAamino terminus of LF fused to the catalytic domain of diphtheria toxinD4domain 4VWAvon Willebrand factor type A domain.1The abbreviations used are: PAprotective antigenELISAenzymelinked immunosorbent assayGFPgreen fluorescent proteinEGFPenhanced green fluorescent proteinATRanthrax toxin receptorMIDASmetal ion-dependent adhesion siteTBSTris-buffered salineCHOChinese hamster ovaryEFedema factorLFlethal factorLFN-DTAamino terminus of LF fused to the catalytic domain of diphtheria toxinD4domain 4VWAvon Willebrand factor type A domain. and two catalytic moieties, edema factor (EF) and lethal factor (LF). EF is an adenylate cyclase that disrupts water homeostasis and impairs immune function in the host (1.Leppla S.H. Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 3162-3166Crossref PubMed Scopus (756) Google Scholar, 2.O'Brien J. Friedlander A. Dreier T. Ezzell J. Leppla S. Infect. Immun. 1985; 47: 306-310Crossref PubMed Google Scholar). LF is a Zn2+-dependent metalloproteinase that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family of protein kinases and disrupts signal transduction pathways (3.Duesbery N.S. Webb C.P. Leppla S.H. Gordon V.M. Klimpel K.R. Copeland T.D. Ahn N.G. Oskarsson M.K. Fukasawa K. Paull K.D. Vande Woude G.F. Science. 1998; 280: 734-737Crossref PubMed Scopus (884) Google Scholar, 4.Pellizzari R. Guidi-Rontani C. Vitale G. Mock M. Montecucco C. FEBS Lett. 1999; 462: 199-204Crossref PubMed Scopus (254) Google Scholar, 5.Vitale G. Pellizzari R. Recchi C. Napolitani G. Mock M. Montecucco C. Biochem. Biophys. Res. Commun. 1998; 248: 706-711Crossref PubMed Scopus (361) Google Scholar, 6.Park J.M. Greten F.R. Li Z.W. Karin M. Science. 2002; 297: 2048-2051Crossref PubMed Scopus (419) Google Scholar). PA binds EF and LF to target cells and transports these catalytic subunits into the host cell cytosol where they carry out their enzymatic functions. A cellular receptor that binds PA as anthrax toxin receptor a protein by the J. M. PubMed Scopus Google Scholar). a cellular receptor PA as the protein Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). PA binds directly to the extracellular integrin-like inserted (I) in and J. M. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the binding of PA to the domain is dependent on the presence of divalent as to this interaction J. M. PubMed Scopus Google Scholar). protective antigen immunosorbent green fluorescent protein green fluorescent protein anthrax toxin receptor metal ion-dependent adhesion site hamster edema factor lethal factor terminus of LF fused to the catalytic domain of diphtheria toxin domain Willebrand factor type A domain. protective antigen immunosorbent green fluorescent protein green fluorescent protein anthrax toxin receptor metal ion-dependent adhesion site hamster edema factor lethal factor terminus of LF fused to the catalytic domain of diphtheria toxin domain Willebrand factor type A domain. of the and these major in the a MIDAS by the is which to binding coordination of a divalent metal R. PubMed Scopus Google Scholar, M. J. Biophys. 2002; PubMed Scopus Google Scholar). domain directly the the metal these integrin-ligand M. J. Biophys. 2002; PubMed Scopus Google Scholar). The domain a MIDAS that we a in the binding of this we in the MIDAS of ATR, a carboxylate group in and specific divalent that that anthrax toxin binds in a that is to the binding and their and of to to the and into the J. M. PubMed Scopus Google and and their and by of the by into the and of by of the of to and this the and of The and of this to the and and their The into cells cells and from the by a and and by and to on the of the the type and to a site and a protein of that the of the of type and in protein by to of and and by and to by on and a by to and and their used to and The PA in these and type and PA in and as J. S. 1998; PubMed Scopus Google of type and of into cells transduction by cells of of protein from and of ATR, J. M. PubMed Scopus Google Scholar). by to cell in the presence of by binding of in to well of a in a of in the presence of of in as a of a the by a cells their to PA binding in a the of and a to J. M. PubMed Scopus Google Scholar). The of protein by and the of PA binding by by of on and to in the presence of and The as well as of on and of cells of on The and cells three in and in and and an of protein from to The in and by by an and an in a of and cells on a cell the cell the by The in and the and of to to the and into the J. M. PubMed Scopus Google and and their and by of the by into the and of by of the of to and this the and of The and of this to the and and their The into cells cells and from the by a and and by and to on the of the the type and to a site and a protein of that the of the of type and in protein by to of and and by and to by on and a PA by to and and their used to and The PA in these and type and PA in and as J. S. 1998; PubMed Scopus Google Scholar). of type and of into cells transduction by cells of of protein from and of ATR, J. M. PubMed Scopus Google Scholar). by to cell in the presence of by binding of in to well of a in a of in the presence of of in as a of a the by a cells their to PA binding in a the of and a to J. M. PubMed Scopus Google Scholar). The of protein by and the of PA binding by by of on and to in the presence of and The as well as of on and of cells of on The and cells three in and in and and an of protein from to The in and by by an and an in a of and cells on a cell the cell the by The in and the the MIDAS in the of the MIDAS in PA we first used an to the specific metal in the toxin-receptor The of a PA by an of the domain in the presence of divalent cations. of PA to by binding the integrin-ligand M. J. Biophys. 2002; PubMed Scopus Google Scholar, A. Biophys. PubMed Scopus Google to toxin-receptor binding binding dependent on the of toxin binding toxin binding from to directly the of the MIDAS in toxin the first of this an to to metal coordination and binding in M. PubMed Scopus Google Scholar, T. J. PubMed Google Scholar, T. R. J. PubMed Scopus Google Scholar, C.P. M. T. J. PubMed Scopus Google Scholar). The into and this to binding to PA in an of the cause of the as by can that in their M. T. A. R. A. J. PubMed Scopus Google Scholar). The MIDAS a to the metal in the in the the is to metal coordination and of the MIDAS in is to the domain into a that an PubMed Scopus Google Scholar, R. J. 1998; PubMed Scopus Google Scholar). a the MIDAS in PA the into the protein disrupts toxin-receptor interaction as by the of the protein a to type that this cause the of of to as a on the and into an green fluorescent protein and the in hamster cells that anthrax toxin J. M. PubMed Scopus Google Scholar). The cell their to toxin binding in a type cells PA and a the of receptor and the of PA cells to PA cells an to PA binding in this that an intact MIDAS is toxin that of on the cell the that the toxin binding to cells A. PubMed Scopus Google Scholar, A. PubMed Scopus Google we the and the of to cells type MIDAS of their to a anthrax toxin PA and the terminus of LF fused to the catalytic domain of diphtheria toxin J. M. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). cells type by this toxin, cells to toxin and cells to toxin type that of the MIDAS toxin receptor a of receptor as seen cell binding and A and this a in PA a divalent and the MIDAS in toxin we PA contributes to the interaction that to the of that to binding by the coordination of the MIDAS metal by of their carboxylate R. PubMed Scopus Google Scholar, M. T. A. R. A. J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J.M. PubMed Scopus Google Scholar). PA a domain we the of PA and that to binding C. Klimpel K.R. Leppla S.H. PubMed Scopus Google Scholar). in the receptor-binding domain and to the to and to PA in and to function in a cell three as a to in cell of the type and the PA that this PA is Asp-683 as a PA of PA domain carboxylate in carboxylate on the as which to in binding J. M. PubMed Scopus Google Scholar, M. Leppla S.H. J. PubMed Google Scholar, M. A. J.M. Leppla S.H. 1998; PubMed Google Scholar). R. M. K. J. Scopus Google in PA is receptor cells to and of type PA to and protein by by an A that of protein in the toxin function the of receptor we this into a receptor-binding domain of PA J. M. PubMed Scopus Google and the of this protein to in a to to a Asp-683 in receptor A the MIDAS in the of the MIDAS in PA we first used an to the specific metal in the toxin-receptor The of a PA by an of the domain in the presence of divalent cations. of PA to by binding the integrin-ligand M. J. Biophys. 2002; PubMed Scopus Google Scholar, A. Biophys. PubMed Scopus Google to toxin-receptor binding binding dependent on the of toxin binding toxin binding from to directly the of the MIDAS in toxin the first of this an to to metal coordination and binding in M. PubMed Scopus Google Scholar, T. J. PubMed Google Scholar, T. R. J. PubMed Scopus Google Scholar, C.P. M. T. J. PubMed Scopus Google Scholar). The into and this to binding to PA in an of the cause of the as by can that in their M. T. A. R. A. J. PubMed Scopus Google Scholar). The MIDAS a to the metal in the in the the is to metal coordination and of the MIDAS in is to the domain into a that an PubMed Scopus Google Scholar, R. J. 1998; PubMed Scopus Google Scholar). a the MIDAS in PA the into the protein disrupts toxin-receptor interaction as by the of the protein a to type that this cause the of of to as a on the and into an green fluorescent protein and the in hamster cells that anthrax toxin J. M. PubMed Scopus Google Scholar). The cell their to toxin binding in a type cells PA and a the of receptor and the of PA cells to PA cells an to PA binding in this that an intact MIDAS is toxin that of on the cell the that the toxin binding to cells A. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar). we the and the of to cells type MIDAS of their to a anthrax toxin PA and the terminus of LF fused to the catalytic domain of diphtheria toxin J. M. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). cells type by this toxin, cells to toxin and cells to toxin type that of the MIDAS toxin receptor a of receptor as seen cell binding and A and this a in PA a divalent and the MIDAS in toxin we PA contributes to the interaction that to the of that to binding by the coordination of the MIDAS metal by of their carboxylate R. PubMed Scopus Google Scholar, M. T. A. R. A. J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J.M. PubMed Scopus Google Scholar). PA a domain we the of PA and that to binding C. Klimpel K.R. Leppla S.H. PubMed Scopus Google Scholar). in the receptor-binding domain and to the to and to PA in and to function in a cell three as a to in cell of the type and the PA that this PA is Asp-683 as a PA the toxin function the of receptor we this into a receptor-binding domain of PA J. M. PubMed Scopus Google and the of this protein to in a to to a Asp-683 in receptor anthrax in is an to and the the receptor binding domain of PA S. J. Infect. Immun. 2002; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of to anthrax PubMed Scopus Google Scholar, S. Infect. Immun. 2002; PubMed Scopus Google Scholar, Friedlander Infect. Immun. PubMed Google Scholar). to binding of PA to cellular to of anthrax of by a of PA cellular The of this to of anthrax by the of the binds directly to the extracellular of ATR, which an integrin-like inserted as a Willebrand factor type A domain that of and function as interaction 2002; PubMed Scopus Google Scholar). in in and an in to extracellular 2002; PubMed Scopus Google Scholar). extracellular domain and and the in these directly to cell adhesion and extracellular 2002; PubMed Scopus Google Scholar, Sci. 1998; PubMed Scopus Google Scholar). the function of is is that the domain as a interaction the function of which is to on an intact The an intact MIDAS toxin binding that PA binding to PA binding is by the an in a is a of domain Asp-683 is in an in which in receptor binding C. Klimpel K.R. Leppla S.H. PubMed Scopus Google Scholar, M. S. Leppla S.H. Infect. Immun. 1999; PubMed Google Scholar). we and J. M. PubMed Scopus Google Scholar, M. S. Leppla S.H. Infect. Immun. 1999; PubMed Google as the of this M. Leppla S.H. J. PubMed Google that Asp-683 in PA in a in which is a of PA binding to cell that Asp-683 two and that Asp-683 is the into of to their requires divalent an intact and the presence of a in a in the the toxin-receptor binding on the an intact MIDAS in ATR, and the an in an in PA we propose that PA is mimicking a domain and that the receptor binding function of Asp-683 coordination of the metal in ATR. anthrax in is an to and the the receptor binding domain of PA S. J. Infect. Immun. 2002; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of to anthrax PubMed Scopus Google Scholar, S. Infect. Immun. 2002; PubMed Scopus Google Scholar, Friedlander Infect. Immun. PubMed Google Scholar). to binding of PA to cellular to of anthrax of by a of PA cellular The of this to of anthrax by the of the PA binds directly to the extracellular of ATR, which an integrin-like inserted as a Willebrand factor type A domain that of and function as interaction 2002; PubMed Scopus Google Scholar). in in and an in to extracellular 2002; PubMed Scopus Google Scholar). extracellular domain and and the in these directly to cell adhesion and extracellular 2002; PubMed Scopus Google Scholar, Sci. 1998; PubMed Scopus Google Scholar). the function of is is that the domain as a interaction the function of which is to on an intact The an intact MIDAS toxin binding that PA binding to ATR. PA binding is by the an in a is a of domain Asp-683 is in an in which in receptor binding C. Klimpel K.R. Leppla S.H. PubMed Scopus Google Scholar, M. S. Leppla S.H. Infect. Immun. 1999; PubMed Google Scholar). we and J. M. PubMed Scopus Google Scholar, M. S. Leppla S.H. Infect. Immun. 1999; PubMed Google as the of this M. Leppla S.H. J. PubMed Google that Asp-683 in PA in a in which is a of PA binding to cell The that Asp-683 two and that Asp-683 is the into of to their requires divalent an intact and the presence of a in a in the the toxin-receptor binding on the an intact MIDAS in ATR, and the an in an in PA we propose that PA is mimicking a domain and that the receptor binding function of Asp-683 coordination of the metal in ATR. We R. J. and M. of the

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