Key points are not available for this paper at this time.
Bile acids are important for digestion of food and antimicrobial activity. Pathogenic Vibrio parahaemolyticus senses bile acids and induce pathogenesis. The bile acid taurodeoxycholate (TDC) was shown to activate the master regulator, VtrB, of this system, whereas other bile acids such as chenodeoxycholate (CDC) do not. Previously, VtrA–VtrC was discovered to be the co-component signal transduction system that binds bile acids and induces pathogenesis. TDC binds to the periplasmic domain of the VtrA–VtrC complex, activating a DNA-binding domain in VtrA that then activates VtrB. Here, we find that CDC and TDC compete for binding to the VtrA–VtrC periplasmic heterodimer. Our crystal structure of the VtrA–VtrC heterodimer bound to CDC revealed CDC binds in the same hydrophobic pocket as TDC but differently. Using isothermal titration calorimetry, we observed that most mutants in the binding pocket of VtrA–VtrC caused a decrease in bile acid binding affinity. Notably, two mutants in VtrC bound bile acids with a similar affinity as the WT protein but were attenuated for TDC-induced type III secretion system 2 activation. Collectively, these studies provide a molecular explanation for the selective pathogenic signaling by V. parahaemolyticus and reveal insight into a host’s susceptibility to disease. Bile acids are important for digestion of food and antimicrobial activity. Pathogenic Vibrio parahaemolyticus senses bile acids and induce pathogenesis. The bile acid taurodeoxycholate (TDC) was shown to activate the master regulator, VtrB, of this system, whereas other bile acids such as chenodeoxycholate (CDC) do not. Previously, VtrA–VtrC was discovered to be the co-component signal transduction system that binds bile acids and induces pathogenesis. TDC binds to the periplasmic domain of the VtrA–VtrC complex, activating a DNA-binding domain in VtrA that then activates VtrB. Here, we find that CDC and TDC compete for binding to the VtrA–VtrC periplasmic heterodimer. Our crystal structure of the VtrA–VtrC heterodimer bound to CDC revealed CDC binds in the same hydrophobic pocket as TDC but differently. Using isothermal titration calorimetry, we observed that most mutants in the binding pocket of VtrA–VtrC caused a decrease in bile acid binding affinity. Notably, two mutants in VtrC bound bile acids with a similar affinity as the WT protein but were attenuated for TDC-induced type III secretion system 2 activation. Collectively, these studies provide a molecular explanation for the selective pathogenic signaling by V. parahaemolyticus and reveal insight into a host’s susceptibility to disease. Vibrio parahaemolyticus is a gram-negative pathogen that is a leading cause of gastroenteritis from the consumption of contaminated raw seafood around the world (1de Souza Santos M. Salomon D. Li P. Krachler A.-M. Orth K. 8 - Vibrio parahaemolyticus virulence determinants.in: Alouf J. Ladant D. Popoff M.R. The Comprehensive Sourcebook of Bacterial Protein Toxins. Fourth Edition. Academic Press, Boston2015: 230-260Crossref Scopus (10) Google Scholar). Many cellular factors contribute to the virulence of V. parahaemolyticus, including two thermostable hemolysins and two type III secretion systems (T3SSs), known as T3SS1 and T3SS2 (1de Souza Santos M. Salomon D. Li P. Krachler A.-M. Orth K. 8 - Vibrio parahaemolyticus virulence determinants.in: Alouf J. Ladant D. Popoff M.R. The Comprehensive Sourcebook of Bacterial Protein Toxins. Fourth Edition. Academic Press, Boston2015: 230-260Crossref Scopus (10) Google Scholar). The T3SSs are large needle-like protein complexes that transport bacterial effector proteins, known as Vops, from the bacterial cytoplasm into the host cell cytoplasm to promote infection (1de Souza Santos M. Salomon D. Li P. Krachler A.-M. Orth K. 8 - Vibrio parahaemolyticus virulence determinants.in: Alouf J. Ladant D. Popoff M.R. The Comprehensive Sourcebook of Bacterial Protein Toxins. Fourth Edition. Academic Press, Boston2015: 230-260Crossref Scopus (10) Google Scholar). The T3SS2 is found only in clinical isolates, and its presence coincides with gastroenteritis as well as with bacterial invasion and intracellular replication in the host gut epithelium (1de Souza Santos M. Salomon D. Li P. Krachler A.-M. Orth K. 8 - Vibrio parahaemolyticus virulence determinants.in: Alouf J. Ladant D. Popoff M.R. The Comprehensive Sourcebook of Bacterial Protein Toxins. Fourth Edition. Academic Press, Boston2015: 230-260Crossref Scopus (10) Google Scholar, 2Zhang L. Krachler A.M. Broberg C.A. Li Y. Mirzaei H. Gilpin C.J. et al.Type III effector VopC mediates invasion for Vibrio species.Cell Rep. 2012; 1: 453-460Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 3de Souza Santos M. Orth K. Intracellular Vibrio parahaemolyticus escapes the vacuole and establishes a replicative niche in the cytosol of epithelial cells.mBio. 2014; 5e01506-01514Crossref PubMed Scopus (37) Google Scholar). T3SS2 expression is regulated by VtrA–VtrC, a member of a newly described superfamily of bacterial “co-component” signaling systems (4Kinch L.N. Cong Q. Jaishankar J. Orth K. Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria.Proc. Natl. Acad. Sci. U. S. A. 2022; 119e2203176119Crossref PubMed Scopus (6) Google Scholar). VtrA–VtrC respond to bile acids in the host intestinal tract and induce expression of VtrB, another inner membrane transcription factor. VtrB then induces expression of the T3SS2 (5Kodama T. Gotoh K. Hiyoshi H. Morita M. Izutsu K. Akeda Y. et al.Two regulators of Vibrio parahaemolyticus play important roles in enterotoxicity by controlling the expression of genes in the Vp-PAI region.PLoS One. 2010; 5e8678Crossref Scopus (50) Google Scholar, 6Gotoh K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google Scholar). The newly described VtrA–VtrC-like superfamily of co-component signaling systems in enteric pathogens include members like ToxR/ToxS and TcpP/TcpH in Vibrio cholerae and PsaE/PsaF in Yersinia pestis (4Kinch L.N. Cong Q. Jaishankar J. Orth K. Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria.Proc. Natl. Acad. Sci. U. S. A. 2022; 119e2203176119Crossref PubMed Scopus (6) Google Scholar). Members of this family share several characteristics where the components of these signaling systems adopt similar domain organizations. The transcription factor component (VtrA) includes an N-terminal helix–turn–helix DNA-binding domain (DBD), a single transmembrane helix, and a C-terminal periplasmic whereas the component includes a transmembrane by a periplasmic The genes share a similar and gene are to an heterodimer of the periplasmic (4Kinch L.N. Cong Q. Jaishankar J. Orth K. Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria.Proc. Natl. Acad. Sci. U. S. A. 2022; 119e2203176119Crossref PubMed Scopus (6) Google Scholar, P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). the of VtrA–VtrC, VtrA as a transcription whereas VtrC in with VtrA senses VtrA–VtrC bile acids in the the VtrA is in the cytoplasm P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar, R. S. T. Vibrio parahaemolyticus VtrA is a and is One. Scopus Google Scholar). characteristics co-component membrane signaling systems from a of systems by the (4Kinch L.N. Cong Q. Jaishankar J. Orth K. Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria.Proc. Natl. Acad. Sci. U. S. A. 2022; 119e2203176119Crossref PubMed Scopus (6) Google Scholar, A. S. R. T. R. J. et of the DNA-binding domain of a transmembrane Rep. PubMed Scopus Google as well as from systems an intracellular for signaling A. R. into the of PubMed Scopus Google Scholar). Previously, V. parahaemolyticus VtrA–VtrC was shown to virulence by the presence of host intestinal bile acids K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google Scholar, P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). of bile acids such as taurodeoxycholate (TDC) induce VtrB expression and T3SS2 but such as chenodeoxycholate (CDC) do K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google Scholar, P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). The molecular the of VtrB expression by bile acids is Here, we isothermal titration to that the bile acid CDC binds to the VtrA–VtrC periplasmic with a similar affinity as with then the structure of the VtrA–VtrC bound with CDC and observed that CDC binds in the same hydrophobic pocket of the VtrA–VtrC as the two bile acids compete to induce VtrB revealed that TDC and CDC of with the VtrA–VtrC Many of the bile pocket binding of TDC and CDC to VtrA–VtrC as well as VtrB expression by in binding but and the provide a molecular explanation for the TDC and CDC VtrB expression and the pathogenic The of the bile acids TDC and CDC share a to a to the are a and a to the The of TDC and CDC in the of an to the TDC a whereas CDC a The of CDC with a acid and the of TDC is to a in a with M. The and PubMed Scopus Google Scholar). the of the in CDC and the be to as for CDC and for of the in the of TDC and we that CDC the same hydrophobic pocket in VtrA–VtrC as bound by in the of the and the of the in TDC and CDC to with VtrA–VtrC and in VtrB transcription CDC binds to the VtrA–VtrC periplasmic domain TDC P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google were titration of CDC into the VtrA–VtrC CDC binds to the in an The of the CDC and VtrA–VtrC was with a of and The of the TDC and VtrA–VtrC was P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). we the with TDC and VtrA–VtrC, we a of and this CDC bound to VtrA–VtrC with a affinity with of TDC and CDC binding with VtrA–VtrC by in affinity with in a Gotoh et K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google that TDC and CDC the of VtrB. we observed that CDC and TDC to VtrA–VtrC, we the two bile acids compete to activate VtrB an attenuated V. parahaemolyticus clinical that is for hemolysins and a the of the VtrB this in with TDC and of CDC from to of expression revealed VtrB is with TDC VtrB expression with the of of CDC the V. parahaemolyticus was in with CDC and of TDC from to VtrB was with CDC VtrB expression with the of of TDC that TDC and CDC compete to induce VtrB The of TDC and CDC VtrB expression these bile acids to the same of the VtrA–VtrC periplasmic domain in the presence of this in and the The crystal structure was molecular with the structure as a and to a of The VtrA–VtrC VtrA–VtrC bound with CDC the and CDC is with an that is in TDC CDC a with a that is by VtrC and The of VtrC a with the of and VtrC with for CDC and the binding pocket was in two of the VtrA–VtrC The for the with and a in the binding whereas the other not. the and was similar in from to The CDC binding with the TDC with the the The of bile acid in a of the two with the of TDC the The of VtrA is similar in of in the a in the of the VtrC in heterodimer with the other and was from the CDC binding in heterodimer with a in the crystal the other the other of the VtrA–VtrC the VtrC of the with VtrA this is VtrC a with CDC is the VtrA in the VtrA–VtrC is a VtrC to The of this similar in the CDC binding and the VtrA The of VtrA the from to whereas the of VtrC from to VtrA and VtrC in and the with the other from to for The structure revealed a with VtrC that of the in the presence of P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). the the of TDC a with VtrC and VtrC and a of a as is observed in the structure The of a with TDC similar to that observed in with the from of the and with the factors revealed in and the and the of CDC the the and as with the where a The a with the of is in CDC the and in the structure that the with the and the from CDC The from the are in a of the in the of the crystal and The of the is by crystal and from the CDC binding in heterodimer with the in the and the of the this be the a with TDC in two of the in the the other heterodimer of the and an are of P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). the of the in the in the that the TDC and the the binding the of a CDC and in the and by the crystal in the VtrA–VtrC structure P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google the is and the is with the of and the pocket in the of bile to binding VtrA–VtrC structure with binding pocket are by The bile acid binding pocket is by the with the of the of the bile acid and the the bile acid and a similar as in the structure bound to TDC The of TDC a with in the in structure bound to CDC establishes a to the of CDC an for WT and from to bound a similar for WT and binding to TDC a similar of and to for the and a similar for binding the and the TDC The in for CDC binding to WT is the TDC and CDC are similar in the the WT protein bound to CDC an The of two the bile acid binding of the VtrA–VtrC and the with VtrA in the and and adopt in the two of with other in the and with The VtrC to in the and the this a similar in of the from the with the this in such that VtrC a in VtrA of the VtrC a with the of VtrA the to VtrA and the by and the this and VtrA be important for TDC-induced of VtrB another explanation for these is in the to the and the P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google the of in the bile acid binding pocket to TDC and CDC we of the VtrA–VtrC periplasmic that binding to bile acids be with WT binding and The mutants single acid of and with VtrA–VtrC complexes in then the binding of TDC and CDC to these VtrA–VtrC of the VtrA–VtrC mutants bound TDC and CDC with as shown by to in for TDC and to in for CDC The to this was the a similar for TDC and CDC with WT Using the to bile acid binding is in that of and in to binding the of these in of the and bile provide insight into binding is by and The of WT binding to TDC is its binding to CDC whereas the of binding TDC is binding CDC with these a from the structure is bile acid The from the WT VtrA–VtrC binding to CDC be by the structure the from of in the the from an with the to the include the of the bound TDC with its to with to the for CDC from protein in the and of VtrA–VtrC binding with bile acids by in and to the of and in the of bile in and to the of and in the of bile in and to the of and in the of bile in and to the of and in the of bile in and to the of and in the of bile in a to the in WT bile acid the VtrC the and to The the for TDC and CDC binding with WT as well as the to The in from the from a decrease in of the bile acids and the with that with the WT The of the that the the of the bound of the protein with the bile of the The observed for TDC binding with to CDC binding to the the observed of by binding TDC and of and a in the WT structure and the binding pocket and decrease the of binding to the bile and similar for TDC binding as the WT protein The structure of VtrA–VtrC a where an from the the bile the the the same as in the but with from this The hydrophobic of is by the from the TDC binding the similar for the and WT a similar to binding the in the as to binding the in the The for and TDC in the to the same of the hydrophobic for the its The in for TDC binding to the and mutants this The similar as WT binding but the for the was the the pocket to the of The of the to a with an of the The establishes a and the from CDC and The CDC is in a of the for binding CDC with to the the in for CDC binding is that of TDC in an that the of by the The the of the to from its to hydrophobic The the of TDC binding with the other the the of CDC binding with WT decrease be with the of the the where the the and the of the the and of bile acid binding to WT and VtrC an that the VtrC in for as in and and in and PubMed Scopus Google Scholar). this of by the of the binding of bile acids to WT VtrA–VtrC were by 2 and the bile acids found in TDC is a of VtrB whereas CDC is a K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google Scholar). and and K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google were The bound to VtrA–VtrC with a binding affinity of similar to that of TDC but CDC the of binding was to that of CDC and that of TDC The of and CDC binding be by the in bile a that from in the crystal structure The binding affinity of with that of CDC be by the of binding with CDC binding an that is the of CDC bound to VtrA–VtrC with a binding affinity of is similar to that of TDC and a with TDC the of with the of TDC and the same in as CDC and a of with that of TDC The for this for binding is as and TDC an but the of and other in binding with The a binding affinity of similar to that of CDC The of binding was is to the of for CDC binding an that a similar in the crystal an like TDC a with the of of binding with the of with the of TDC the for the binding of these bile acids reveals two Bile acids with an with with an in the of bile acids with an with with an the of of VtrA–VtrC of molecular bile The the binding affinity of VtrA–VtrC to bile acid the of TDC binding and to a of the of a the TDC and the and the and of CDC binding was similar to that of the WT protein a with CDC and binding to bile acids for the we that the of the by the the of the VtrB transcription factor activation. this we a in a V. parahaemolyticus the single acid of and from a the of an The a with the gene the of the V. parahaemolyticus VtrB R. S. T. Vibrio parahaemolyticus VtrA is a and is One. Scopus Google with the of the VtrB The were with TDC and and were for The were then by and the the are in of with in a decrease in in to TDC with the WT this a in transcription factor in to binding the presence of the similar of that was the The binding of the to TDC and with the selective of VtrB transcription in to but a for the of the in of the VtrA–VtrC transcription factor. of the binding and with in decrease in in to TDC with the WT the the binding pocket P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google similar as the WT WT VtrC and VtrC mutants were similar in the and TDC-induced The was shown to similar of protein with WT VtrC P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). to the for of the WT and with CDC that were from an that the binding pocket are important for of VtrB transcription in to CDC induce transcription of VtrB in of the WT shown in the bile acids TDC and CDC compete to induce VtrB bile acids such as CDC and are in the and to to secretion into the M. The and PubMed Scopus Google Scholar). in the these bile acids such as by bile to bile acids and bile acids like M. The and PubMed Scopus Google Scholar). and bile acids are from the and in the M. The and PubMed Scopus Google Scholar, The of bile acids in and intestinal PubMed Scopus Google bile acids like of the bile such as were observed as of VtrB whereas the bile acids CDC and do induce transcription K. Kodama T. Hiyoshi H. Izutsu K. Park K.-S. Dryselius R. et al.Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.PLoS One. 2010; 5e13365Crossref Scopus (90) Google Scholar). bile acids and induce of these the of VtrB the of VtrA–VtrC, known as a co-component signal transduction system that to the bile acid TDC and activates VtrB (4Kinch L.N. Cong Q. Jaishankar J. Orth K. Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria.Proc. Natl. Acad. Sci. U. S. A. 2022; 119e2203176119Crossref PubMed Scopus (6) Google Scholar, P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). The bile acids such as TDC an and an acid to the of the and The bile acids an of for and acids the The bile acids of the a this we the bile acids and The CDC an and with a for transcription binding the of TDC and CDC an that a in the VtrC and the that is important for activating the of in the and the presence of an acid to the are with the of a bile acid to induce VtrB transcription of bile acids by for gut including a of the bacterial membrane of bile acids and the and of bile acids that are to M. The and PubMed Scopus Google Scholar, S. R. Bile of bile acid and in the PubMed Scopus Google Scholar). studies shown that the of bile acids by of provide by enteric pathogens such as V. cholerae and by the of the bile acid in the S. R. A. gut susceptibility and to Full Text Full Text PDF PubMed Scopus Google Scholar, S. et bile 2022; Scopus Google Scholar). the of V. parahaemolyticus, of in the a of bile acids like CDC that T3SS2 the of this we that gut and the of the intestinal bile acid be important for V. parahaemolyticus the host as a a V. parahaemolyticus as the the tract The tract from to in the to to in the and to in the large R. of in PubMed Scopus Google Scholar). we the of VtrA–VtrC in to the and and the in to and the WT the of and was whereas the the was that of the WT the decrease in to a and The was from the similar was for the the was and are important for activating VtrB transcription and that the of VtrB transcription be a of in the binding affinity of TDC and the of binding we with the VtrA–VtrC periplasmic The in were a the then the WT and of the VtrA–VtrC periplasmic in and The binding of TDC and CDC to protein were these same and The for TDC and CDC are in and The WT protein bound TDC with with these were the of other and were the WT protein bound CDC with similar the bound TDC with similar with with that of WT with TDC the bound CDC with a around with of around and the of the of the was to the of the a we the binding affinity of with CDC is with and that the bile acid binding of the WT and do The of VtrB transcription are a of in bile acid the bile acid binding the of the VtrA–VtrC protein in to The of the is the of in is well known and to be H. and of protein PubMed Scopus Google Scholar). the of in a protein of from the of the in the protein and with H. and of protein PubMed Scopus Google Scholar). The M. of and in PubMed Scopus Google Scholar, M. of and in and of PubMed Scopus Google this to be the for the The of was in the in the and in the The structure was in the structure in P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google and the structure in the the caused by the a is in the protein The the of and the of M. of and in PubMed Scopus Google Scholar). to VtrC was in the in the and in the with the of in the crystal the is by the the the this is but is by TDC binding the the of is from of the with a and is the similar and of in the and we that the VtrA–VtrC for activation. of the by TDC binding and of a TDC and VtrA–VtrC is CDC binds to VtrA–VtrC, the protein is for the of is by the presence of a and the do provide an explanation for VtrA–VtrC induces transcription binding TDC and but The of for in the structure is the we this be in of VtrA–VtrC and of VtrA–VtrC are with the titration of TDC binding by for the periplasmic the in the only the periplasmic of are of VtrA–VtrC, the of the protein is that expression of VtrA with the was to activate VtrB whereas a the VtrA transmembrane domain and the was R. S. T. Vibrio parahaemolyticus VtrA is a and is One. Scopus Google Scholar). that VtrA–VtrC an of in the TDC this of to activate the for a of be in the crystal of the VtrA–VtrC periplasmic P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google Scholar). crystal and of in the crystal P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google with K. of from PubMed Scopus Google that this is in K. of from PubMed Scopus Google of the P. L.N. Salomon D. et al.Bile activates a pathogenic type III secretion Scopus Google and that the VtrA–VtrC periplasmic heterodimer was the only structure in for The of a of in the periplasmic TDC binding cause a in the to activate the we the molecular of TDC and CDC that the co-component signaling system VtrA–VtrC activate VtrB and the pathogenic T3SS2 CDC and TDC to the same hydrophobic pocket in the VtrA–VtrC periplasmic domain but with binding pocket and binding of VtrA–VtrC mutants that the VtrC and and the TDC and are important for activating VtrB transcription and The TDC and is important for binding of the bile and its the of CDC the to to an in these two and the to CDC and is and CDC CDC an of an and The of to the and bound to TDC but CDC the the two bile acids for activating VtrB transcription of this binding to TDC but the and the of VtrA–VtrC to activate transcription of VtrB the of the for activate The VtrA–VtrC transcription factor the of the in the to for transcription activation. The structure and binding in this are to the periplasmic of VtrA–VtrC and of binding to the periplasmic with transcription by the VtrA–VtrC studies are to the molecular of the of TDC and of CDC in the of
Zou et al. (Tue,) studied this question.