Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
twitter

MetaCyc Protein: MazF toxin of the MazF-MazE toxin-antitoxin system that exhibits ribonuclease activity

Gene: chpA Accession Numbers: EG11249 (MetaCyc), b2782, ECK2776

Synonyms: chpAK, mazF

Species: Escherichia coli K-12 substr. MG1655

Component of: MazE-MazF complex

Subunit composition of MazF toxin of the MazF-MazE toxin-antitoxin system that exhibits ribonuclease activity = [ChpA]2
         MazF toxin of the MazF-MazE toxin-antitoxin system that exhibits ribonuclease activity = ChpA

Summary:
MazF is a toxin that is counteracted by the MazE antitoxin [Masuda93, Aizenman96]. MazF exhibits sequence-specific ribonuclease activity toward single- or double-stranded RNA regions [MunozGomez04], and the resulting degradation of cellular mRNA causes global translation inhibition [Zhang03]. MazF exhibits RNase activity toward tmRNA, and tmRNA is involved in release of MazF-mediated cell growth inhibition [Christensen03]. MazF also stimulates DNA binding by MazE [Zhang03a].

In complex with MazE, MazF is a negative DNA-binding transcriptional regulator of cell growth. It regulates its own synthesis by negatively controlling the expression of the mazEF operon [Marianovsky01]. MazF belongs to the PemK family.

The MazEF system causes a "programmed cell death" response to stresses including starvation [Aizenman96] and antibiotics [Sat01]. The antitoxin, MazE, is subject to degradation by ClpAP protease complex and exhibits a short (30 minute) half life, whereas the toxin, MazF, is much more stable [Aizenman96]. Overproduction of MazE has no effect in the absence of MazF [Aizenman96].

Published reports disagree about whether MazF causes cell lysis in the absence of MazE [Aizenman96] or whether the toxin causes reversible inhibition of cell growth, inhibiting translation and replication without causing cell inviability [Pedersen02]. The MazE-MazF system mediates the toxicity of guanosine 3',5'-bispyrophosphate (rapid relA induction), which is associated with amino acid deprivation [Aizenman96]; cell death caused by the antibiotics rifampicin, chloramphenicol, and spectinomycin [Sat01]; and the thymineless death (TLD) response to thymine starvation [Sat03].

The structure of the MazE-MazF complex is presented at 1.7 Å resolution [Kamada03]. The complex is hexameric and is comprised of a MazE homodimer sandwiched between MazF homodimers [Kamada03]. It is proposed that the MazE monomer is less stably folded than the homodimer and that dimerization and associated structural changes may have an important role in protein activity [Lah03].

Protein-protein interactions in the MazE-MazF complex are discussed [Kamada03, Zhang03a]. MazE and MazF comigrate during native gel electrophoresis [Aizenman96]. The MazE N terminus may be involved in interaction with MazF [SantosSierra97]. The MazE-DNA interaction has been characterized [Lah03].

Homology and genomic organization of similar antitoxin/toxin systems among bacteria has been reviewed [Mittenhuber99]. MazF has similarity to episomal PemK [Masuda93].

Transcription of mazF is induced by starvation of amino acids [Christensen03]. Transcription of the mazEF "addiction module" is repressed by high concentrations of guanosine 3',5'-bispyrophosphate (ppGpp), suggesting that amino acid starvation induces lethality via RelA and the MazE-MazF system [Aizenman96]. Thymine deprivation also represses mazEF transcription [Sat03]. An autoinhibitory effect on transcription has been observed and an inversion mechanism also contributes to transcriptional regulation [Marianovsky01]. The lambda RexB protein has an inhibitory effect on ClpP-mediated proteolysis of MazE, increasing survival of lysogenized cells under conditions of amino acid deprivation [EngelbergKulka98].

Reviews: [Mittenhuber99, delaCuevaMendez03, Yamaguchi11]

Locations: cytosol

Map Position: [2,908,778 <- 2,909,113]

Unification Links: ASAP:ABE-0009119 , CGSC:33287 , DisProt:DP00299 , EchoBASE:EB1229 , EcoGene:EG11249 , EcoliWiki:b2782 , ModBase:P0AE70 , OU-Microarray:b2782 , PortEco:b2782 , PR:PRO_000022284 , Protein Model Portal:P0AE70 , RefSeq:NP_417262 , RegulonDB:EG11249 , SMR:P0AE70 , String:511145.b2782 , Swiss-Model:P0AE70 , UniProt:P0AE70

Relationship Links: InterPro:IN-FAMILY:IPR003477 , InterPro:IN-FAMILY:IPR011067 , PDB:Structure:1UB4 , PDB:Structure:3NFC , Pfam:IN-FAMILY:PF02452

Ortholog Links: EcoO157Cyc (Escherichia coli O157:H7 str. EDL933):CHPA

Gene-Reaction Schematic: ?

GO Terms:

Biological Process: GO:0030308 - negative regulation of cell growth Inferred from experiment [Aizenman96]
GO:0043488 - regulation of mRNA stability Inferred from experiment [Christensen03]
GO:0090502 - RNA phosphodiester bond hydrolysis, endonucleolytic Inferred from experiment [Christensen03]
GO:0006351 - transcription, DNA-templated Inferred by computational analysis [UniProtGOA11]
GO:0006355 - regulation of transcription, DNA-templated Inferred by computational analysis [UniProtGOA11]
GO:0006950 - response to stress Inferred by computational analysis [UniProtGOA11]
GO:0009372 - quorum sensing Inferred by computational analysis [UniProtGOA11]
GO:0090305 - nucleic acid phosphodiester bond hydrolysis Inferred by computational analysis [UniProtGOA11]
Molecular Function: GO:0004521 - endoribonuclease activity Inferred from experiment [Christensen03]
GO:0005515 - protein binding Inferred from experiment [Aizenman96]
GO:0003677 - DNA binding Inferred by computational analysis [UniProtGOA11, GOA01]
GO:0003723 - RNA binding Inferred by computational analysis [UniProtGOA11]
GO:0004518 - nuclease activity Inferred by computational analysis [UniProtGOA11]
GO:0004519 - endonuclease activity Inferred by computational analysis [UniProtGOA11]
GO:0016787 - hydrolase activity Inferred by computational analysis [UniProtGOA11]
Cellular Component: GO:0005829 - cytosol Inferred by computational analysis [DiazMejia09]

MultiFun Terms: cell processes adaptations other (mechanical, nutritional, oxidative stress)
cell processes adaptations starvation
cell processes defense/survival
cell processes protection cell killing
cell processes protection drug resistance/sensitivity
information transfer protein related translation
information transfer RNA related RNA degradation
regulation type of regulation posttranscriptional translation attenuation and efficiency


Subunit of: MazE-MazF complex

Synonyms: MazE-MazF "addiction module", MazFE, MazEF

Species: Escherichia coli K-12 substr. MG1655

Subunit composition of MazE-MazF complex = [(ChpA)2]2[(ChpR)2]
         MazF toxin of the MazF-MazE toxin-antitoxin system that exhibits ribonuclease activity = (ChpA)2
                 MazF toxin of the MazF-MazE toxin-antitoxin system that exhibits ribonuclease activity = ChpA
         MazE antitoxin of the MazF-MazE toxin-antitoxin system = (ChpR)2
                 MazE antitoxin of the MazF-MazE toxin-antitoxin system = ChpR

Enzymes inhibited by MazE-MazF complex, sorted by the type of inhibition, are:

Inhibitor (Mechanism unknown) of: nucleoside triphosphate pyrophosphohydrolase [Gross06]


Sequence Features

Feature Class Location Citations Comment
Mutagenesis-Variant 24
[Li06, UniProt11]
Alternate sequence: A; UniProt: Greatly reduces toxicity, about 10- fold less RNA cleavage activity.

History:
10/20/97 Gene b2782 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG11249; confirmed by SwissProt match.


References

Aizenman96: Aizenman E, Engelberg-Kulka H, Glaser G (1996). "An Escherichia coli chromosomal "addiction module" regulated by guanosine [corrected] 3',5'-bispyrophosphate: a model for programmed bacterial cell death." Proc Natl Acad Sci U S A 93(12);6059-63. PMID: 8650219

Christensen03: Christensen SK, Pedersen K, Hansen FG, Gerdes K (2003). "Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA." J Mol Biol 332(4);809-19. PMID: 12972253

delaCuevaMendez03: de la Cueva-Mendez G (2003). "Distressing bacteria: structure of a prokaryotic detox program." Mol Cell 11(4);848-50. PMID: 12718870

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

EngelbergKulka98: Engelberg-Kulka H, Reches M, Narasimhan S, Schoulaker-Schwarz R, Klemes Y, Aizenman E, Glaser G (1998). "rexB of bacteriophage lambda is an anti-cell death gene." Proc Natl Acad Sci U S A 95(26);15481-6. PMID: 9860994

GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

Gross06: Gross M, Marianovsky I, Glaser G (2006). "MazG - a regulator of programmed cell death in Escherichia coli." Mol Microbiol 59(2);590-601. PMID: 16390452

Kamada03: Kamada K, Hanaoka F, Burley SK (2003). "Crystal structure of the MazE/MazF complex: molecular bases of antidote-toxin recognition." Mol Cell 11(4);875-84. PMID: 12718874

Lah03: Lah J, Marianovsky I, Glaser G, Engelberg-Kulka H, Kinne J, Wyns L, Loris R (2003). "Recognition of the intrinsically flexible addiction antidote MazE by a dromedary single domain antibody fragment. Structure, thermodynamics of binding, stability, and influence on interactions with DNA." J Biol Chem 278(16);14101-11. PMID: 12533537

Li06: Li GY, Zhang Y, Chan MC, Mal TK, Hoeflich KP, Inouye M, Ikura M (2006). "Characterization of dual substrate binding sites in the homodimeric structure of Escherichia coli mRNA interferase MazF." J Mol Biol 357(1);139-50. PMID: 16413577

Marianovsky01: Marianovsky I, Aizenman E, Engelberg-Kulka H, Glaser G (2001). "The regulation of the Escherichia coli mazEF promoter involves an unusual alternating palindrome." J Biol Chem 276(8);5975-84. PMID: 11071896

Masuda93: Masuda Y, Miyakawa K, Nishimura Y, Ohtsubo E (1993). "chpA and chpB, Escherichia coli chromosomal homologs of the pem locus responsible for stable maintenance of plasmid R100." J Bacteriol 175(21);6850-6. PMID: 8226627

Mittenhuber99: Mittenhuber G (1999). "Occurrence of mazEF-like antitoxin/toxin systems in bacteria." J Mol Microbiol Biotechnol 1(2);295-302. PMID: 10943559

MunozGomez04: Munoz-Gomez AJ, Santos-Sierra S, Berzal-Herranz A, Lemonnier M, Diaz-Orejas R (2004). "Insights into the specificity of RNA cleavage by the Escherichia coli MazF toxin." FEBS Lett 567(2-3);316-20. PMID: 15178344

Pedersen02: Pedersen K, Christensen SK, Gerdes K (2002). "Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins." Mol Microbiol 45(2);501-10. PMID: 12123459

SantosSierra97: Santos-Sierra S, Giraldo R, Diaz-Orejas R (1997). "Functional interactions between homologous conditional killer systems of plasmid and chromosomal origin." FEMS Microbiol Lett 152(1);51-6. PMID: 9228770

Sat01: Sat B, Hazan R, Fisher T, Khaner H, Glaser G, Engelberg-Kulka H (2001). "Programmed cell death in Escherichia coli: some antibiotics can trigger mazEF lethality." J Bacteriol 183(6);2041-5. PMID: 11222603

Sat03: Sat B, Reches M, Engelberg-Kulka H (2003). "The Escherichia coli mazEF suicide module mediates thymineless death." J Bacteriol 185(6);1803-7. PMID: 12618443

UniProt11: UniProt Consortium (2011). "UniProt version 2011-06 released on 2011-06-30 00:00:00." Database.

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

Yamaguchi11: Yamaguchi Y, Park JH, Inouye M (2011). "Toxin-antitoxin systems in bacteria and archaea." Annu Rev Genet 45;61-79. PMID: 22060041

Zhang03: Zhang Y, Zhang J, Hoeflich KP, Ikura M, Qing G, Inouye M (2003). "MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli." Mol Cell 12(4);913-23. PMID: 14580342

Zhang03a: Zhang J, Zhang Y, Inouye M (2003). "Characterization of the interactions within the mazEF addiction module of Escherichia coli." J Biol Chem 278(34);32300-6. PMID: 12810711


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Nov 23, 2014, biocyc13.