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Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation

Research output: Working paper/Preprint › Preprint

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Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation. / Bærentsen, René; Vang Nielsen, Stine; Lyngsø, Jeppe et al.

bioRxiv, 2022.

Research output: Working paper/Preprint › Preprint

Vancouver

Bærentsen R, Vang Nielsen S, Lyngsø J, Bisiak F, Pedersen JS, Gerdes K et al. Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation. bioRxiv. 2022 Jan. doi: 10.1101/2022.01.28.478185

Author

Bærentsen, René ; Vang Nielsen, Stine ; Lyngsø, Jeppe et al. / Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation. bioRxiv, 2022.

Bibtex

@techreport{9a1814d6a3d6423cb4052a4561d74e79,

title = "Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation",

abstract = "Many bacteria encode multiple toxin-antitoxin (TA) systems targeting separate, but closely related, cellular functions. The toxin of the E. coli hipBA system, HipA, is a kinase that inhibits inhibits translation via phosphorylation of glutamyl-tRNA synthetase. Enteropathogenic E. coli (EPEC) O127:H6 encodes an additional, tripartite TA module, hipBST, for which the HipT toxin was shown to specifically target tryptophanyl-tRNA synthetase, TrpS. Surprisingly, the function as antitoxin has been taken over by the third protein, HipS, but the molecular details of how activity of HipT is controlled remain poorly understood. Here, we show that HipBST is markedly different from HipBA and that the unique HipS protein, which is homologous to the N-terminal subdomain of HipA, has evolved to function as antitoxin by breaking the kinase active site. We also show how auto-phosphorylation at two conserved sites in the kinase toxin serve to dually regulate binding of HipS and kinase activity. Finally, we demonstrate that the HipBST complex is dynamic and present a cohesive model for the regulation and activation of this type of three-component system.",

author = "Ren{\'e} B{\ae}rentsen and {Vang Nielsen}, Stine and Jeppe Lyngs{\o} and Francesco Bisiak and Pedersen, {Jan Skov} and Kenn Gerdes and Michael S{\o}rensen and Brodersen, {Ditlev E.}",

year = "2022",

month = jan,

doi = "10.1101/2022.01.28.478185",

language = "English",

publisher = "bioRxiv",

type = "WorkingPaper",

institution = "bioRxiv",

}

RIS

TY - UNPB

T1 - Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation

AU - Bærentsen, René

AU - Vang Nielsen, Stine

AU - Lyngsø, Jeppe

AU - Bisiak, Francesco

AU - Pedersen, Jan Skov

AU - Gerdes, Kenn

AU - Sørensen, Michael

AU - Brodersen, Ditlev E.

PY - 2022/1

Y1 - 2022/1

N2 - Many bacteria encode multiple toxin-antitoxin (TA) systems targeting separate, but closely related, cellular functions. The toxin of the E. coli hipBA system, HipA, is a kinase that inhibits inhibits translation via phosphorylation of glutamyl-tRNA synthetase. Enteropathogenic E. coli (EPEC) O127:H6 encodes an additional, tripartite TA module, hipBST, for which the HipT toxin was shown to specifically target tryptophanyl-tRNA synthetase, TrpS. Surprisingly, the function as antitoxin has been taken over by the third protein, HipS, but the molecular details of how activity of HipT is controlled remain poorly understood. Here, we show that HipBST is markedly different from HipBA and that the unique HipS protein, which is homologous to the N-terminal subdomain of HipA, has evolved to function as antitoxin by breaking the kinase active site. We also show how auto-phosphorylation at two conserved sites in the kinase toxin serve to dually regulate binding of HipS and kinase activity. Finally, we demonstrate that the HipBST complex is dynamic and present a cohesive model for the regulation and activation of this type of three-component system.

AB - Many bacteria encode multiple toxin-antitoxin (TA) systems targeting separate, but closely related, cellular functions. The toxin of the E. coli hipBA system, HipA, is a kinase that inhibits inhibits translation via phosphorylation of glutamyl-tRNA synthetase. Enteropathogenic E. coli (EPEC) O127:H6 encodes an additional, tripartite TA module, hipBST, for which the HipT toxin was shown to specifically target tryptophanyl-tRNA synthetase, TrpS. Surprisingly, the function as antitoxin has been taken over by the third protein, HipS, but the molecular details of how activity of HipT is controlled remain poorly understood. Here, we show that HipBST is markedly different from HipBA and that the unique HipS protein, which is homologous to the N-terminal subdomain of HipA, has evolved to function as antitoxin by breaking the kinase active site. We also show how auto-phosphorylation at two conserved sites in the kinase toxin serve to dually regulate binding of HipS and kinase activity. Finally, we demonstrate that the HipBST complex is dynamic and present a cohesive model for the regulation and activation of this type of three-component system.

U2 - 10.1101/2022.01.28.478185

DO - 10.1101/2022.01.28.478185

M3 - Preprint

BT - Structural basis for regulation of a tripartite toxin-antitoxin system by dual phosphorylation

PB - bioRxiv

ER -