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Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy.

Cataudella I, Sneppen K, Gerdes K, Mitarai N - PLoS Comput. Biol. (2013)

Bottom Line: Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor.Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers.We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

View Article: PubMed Central - PubMed

Affiliation: Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT
Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined "conditional cooperativity". Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription at low toxin level, strong repression at intermediate toxin level, and then again transcription at high toxin level. Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers. We explore possible functions of conditional regulation in simple feedback motifs, and show that it can provide bistability for a wide range of parameters. We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

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Heterocomplex formation in a TA system.(A) Reaction scheme of the heterocomplex formations, implying that the active complex [AT] is constrained by through  and  with complex concentrations expressed by eq. (2). (B) Concentration of AT heteromers for a fixed value of  as a function of  with . Note that it has a peak at . In the strong binding limit of  with  ( kept constant),  for  is given by  for  and , where  always has a peak at . In this limit,  for . (C) The behavior of  shown in (B) is reflected in the behavior of the repression factor  as a function of , calculated for fixed , and dissociation constant for AT-DNA binding .
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pcbi-1003174-g001: Heterocomplex formation in a TA system.(A) Reaction scheme of the heterocomplex formations, implying that the active complex [AT] is constrained by through and with complex concentrations expressed by eq. (2). (B) Concentration of AT heteromers for a fixed value of as a function of with . Note that it has a peak at . In the strong binding limit of with ( kept constant), for is given by for and , where always has a peak at . In this limit, for . (C) The behavior of shown in (B) is reflected in the behavior of the repression factor as a function of , calculated for fixed , and dissociation constant for AT-DNA binding .

Mentions: We examine a simplified system, where protein A and T can form two kinds of heteromers, AT and ATT (Fig.1A):(1)Here, we assume that AT is the active molecule that act as a transcriptional repressor, whereas free A, free T, and ATT are not active in transcriptional control. This is a simplification of the transcriptional regulation by RelBE, where RelB2 corresponds to one A, while RelE corresponds to one T.


Conditional cooperativity of toxin - antitoxin regulation can mediate bistability between growth and dormancy.

Cataudella I, Sneppen K, Gerdes K, Mitarai N - PLoS Comput. Biol. (2013)

Heterocomplex formation in a TA system.(A) Reaction scheme of the heterocomplex formations, implying that the active complex [AT] is constrained by through  and  with complex concentrations expressed by eq. (2). (B) Concentration of AT heteromers for a fixed value of  as a function of  with . Note that it has a peak at . In the strong binding limit of  with  ( kept constant),  for  is given by  for  and , where  always has a peak at . In this limit,  for . (C) The behavior of  shown in (B) is reflected in the behavior of the repression factor  as a function of , calculated for fixed , and dissociation constant for AT-DNA binding .
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757081&req=5

pcbi-1003174-g001: Heterocomplex formation in a TA system.(A) Reaction scheme of the heterocomplex formations, implying that the active complex [AT] is constrained by through and with complex concentrations expressed by eq. (2). (B) Concentration of AT heteromers for a fixed value of as a function of with . Note that it has a peak at . In the strong binding limit of with ( kept constant), for is given by for and , where always has a peak at . In this limit, for . (C) The behavior of shown in (B) is reflected in the behavior of the repression factor as a function of , calculated for fixed , and dissociation constant for AT-DNA binding .
Mentions: We examine a simplified system, where protein A and T can form two kinds of heteromers, AT and ATT (Fig.1A):(1)Here, we assume that AT is the active molecule that act as a transcriptional repressor, whereas free A, free T, and ATT are not active in transcriptional control. This is a simplification of the transcriptional regulation by RelBE, where RelB2 corresponds to one A, while RelE corresponds to one T.

Bottom Line: Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor.Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers.We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

View Article: PubMed Central - PubMed

Affiliation: Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.

ABSTRACT
Many toxin-antitoxin operons are regulated by the toxin/antitoxin ratio by mechanisms collectively coined "conditional cooperativity". Toxin and antitoxin form heteromers with different stoichiometric ratios, and the complex with the intermediate ratio works best as a transcription repressor. This allows transcription at low toxin level, strong repression at intermediate toxin level, and then again transcription at high toxin level. Such regulation has two interesting features; firstly, it provides a non-monotonous response to the concentration of one of the proteins, and secondly, it opens for ultra-sensitivity mediated by the sequestration of the functioning heteromers. We explore possible functions of conditional regulation in simple feedback motifs, and show that it can provide bistability for a wide range of parameters. We then demonstrate that the conditional cooperativity in toxin-antitoxin systems combined with the growth-inhibition activity of free toxin can mediate bistability between a growing state and a dormant state.

Show MeSH
Related in: MedlinePlus