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

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 [Zhang03e]. MazF exhibits RNase activity toward tmRNA, and tmRNA is involved in release of MazF-mediated cell growth inhibition [Christensen03a]. MazF also stimulates DNA binding by MazE [Zhang03f].

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, Zhang03f]. 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 [Christensen03a]. 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: ?

Gene-Reaction Schematic

GO Terms:

Biological Process: GO:0006402 - mRNA catabolic process Inferred from experiment [Christensen03a]
GO:0016075 - rRNA catabolic process Inferred from experiment [Vesper11]
GO:0030308 - negative regulation of cell growth Inferred from experiment [Aizenman96]
GO:0090502 - RNA phosphodiester bond hydrolysis, endonucleolytic Inferred from experiment [Christensen03a]
GO:0006351 - transcription, DNA-templated Inferred by computational analysis [UniProtGOA11a]
GO:0006355 - regulation of transcription, DNA-templated Inferred by computational analysis [UniProtGOA11a]
GO:0009372 - quorum sensing Inferred by computational analysis [UniProtGOA11a]
GO:0090305 - nucleic acid phosphodiester bond hydrolysis Inferred by computational analysis [UniProtGOA11a]
Molecular Function: GO:0004521 - endoribonuclease activity Inferred from experiment [Christensen03a]
GO:0005515 - protein binding Inferred from experiment [Aizenman96]
GO:0003677 - DNA binding Inferred by computational analysis [UniProtGOA11a, GOA01a]
GO:0003723 - RNA binding Inferred by computational analysis [UniProtGOA11a]
GO:0004518 - nuclease activity Inferred by computational analysis [UniProtGOA11a]
GO:0004519 - endonuclease activity Inferred by computational analysis [UniProtGOA11a]
GO:0016787 - hydrolase activity Inferred by computational analysis [UniProtGOA11a]
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]
UniProt: Greatly reduces toxicity, about 10- fold less RNA cleavage activity.

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


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

Christensen03a: 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

GOA01a: 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.

UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

Vesper11: Vesper O, Amitai S, Belitsky M, Byrgazov K, Kaberdina AC, Engelberg-Kulka H, Moll I (2011). "Selective translation of leaderless mRNAs by specialized ribosomes generated by MazF in Escherichia coli." Cell 147(1);147-57. PMID: 21944167

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

Zhang03e: 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

Zhang03f: 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

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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