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HipB DNA-binding transcriptional repressor

Synonyms: HipB
Summary:
HipB is a transcriptional repressor that functions as the antagonist of HipA, which was the first protein found to mediate the phenomenon of persistence in E. coli. A small fraction of cells within a population are dormant persister cells; these cells are phenotypic variants that are not killed by antibiotics, leading to multidrug tolerance (MDT). Persistence may be ultimately due to global remodeling of the persister cell's ribosomes []. The HipAB system can be categorized as a type II toxin/antitoxin module. In the absence of its binding partner HipB, HipA is toxic to the cell [4, 6, 7]. Above a certain threshold, the level of HipA in the cell determines the typical duration of growth arrest. The threshold level is determined by the level of HipB [7]. The HipAB system appears to be regulated at the level of HipB stability. Degradation of HipB is mainly dependent on the Lon protease, and is dependent on an unstructured 16 amino acid domain at the C terminus of the protein [8]. A variety of crystal structures of HipB in complexes with DNA and HipA have been solved [9, 10, 11, 12].
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
HipB Functional   nd [1], [2]
Evolutionary Family: HTH_3
Connectivity class: Local Regulator
Gene name: hipB
  Genome position: 1592176-1592442
  Length: 267 bp / 88 aa
Operon name: hipBA
TU(s) encoding the TF:
Transcription unit        Promoter
hipBA
hipBp


Regulon       
Regulated gene(s) fadH, hipA, hipB, mazE, mazF, relA
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
translation (2)
defense/survival (2)
starvation (2)
other (mechanical, nutritional, oxidative stress) (2)
cell killing (2)
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Regulated operon(s) fadH, hipBA, relA-mazEFG
First gene in the operon(s) fadH, hipB, relA
Simple and complex regulons ArcA,CRP,FadR,HipB
HipAB,HipB
HipAB,HipB,IHF
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[HipB,-](3)


Transcription factor regulation    


Transcription factor binding sites (TFBSs) arrangements
      

  Functional conformation Function Promoter Sigma factor Central Rel-Pos Distance to first Gene Genes Sequence LeftPos RightPos Evidence (Confirmed, Strong, Weak) References
  HipB repressor fadHp nd -132.5 -173.0 fadH
gtggacgcctTATCCGCCCTACATGTGCAATTCCGTAACCTGGATAaaacgcgaca
3231474 3231510 [BPP], [GEA], [HIBSCS] [3]
  HipB repressor hipBp Sigma70 -85.5 -125.5 hipB, hipA
aaacgctgcgATATCCGCGATCGCGGATAAaaaggaggat
1592558 1592577 [BPP], [GEA], [HIBSCS] [4]
  HipB repressor hipBp Sigma70 -57.5 -97.5 hipB, hipA
gaaacacatcTTATCCGCTCTACGGGATAAacgctgcgat
1592530 1592549 [BPP], [GEA], [HIBSCS] [4]
  HipB repressor hipBp Sigma70 -18.5 -59.0 hipB, hipA
attataagttTTATCCTTTAGTGAGGATAAgtcaatctgg
1592491 1592511 [BPP], [GEA], [HIBSCS] [4]
  HipB repressor hipBp Sigma70 10.5 -30.5 hipB, hipA
cacagcaagtTTATCCGCTTAAGGGGATATtataagtttt
1592463 1592482 [BPP], [GEA], [HIBSCS] [4]
  HipB repressor relAp1 Sigma70 5.0 -174.5 relA, mazE, mazF
aacgcttcgcTATCCCGAGCCAGCGTTGCAGGGTTACAGGATAcataaactat
2913809 2913842 [AIBSCS], [BPP], [GEA] [3]



High-throughput Transcription factor binding sites (TFBSs)
      

  Functional conformation Function Object name Object type Distance to first Gene Sequence LeftPos RightPos Evidence (Confirmed, Strong, Weak) References
  HipB repressor eutHA nd nd 2568161 2568197 [ICWHO], [ITCR] [5]
  HipB repressor eutHA nd nd 2568261 2568297 [ICWHO], [ITCR] [5]


Alignment and PSSM for HipB TFBSs    

Position weight matrix (PWM).   
A	2	0	3	2	2	3	0	4	0	0	2	1	1	1	1	1	4	1	1	0	0	4	0	5	5	5	4	1	0	0
C	1	2	0	1	3	1	1	0	0	6	4	2	5	0	3	0	1	1	3	0	2	0	0	0	0	0	2	1	2	1
G	1	0	3	1	1	0	0	0	2	0	0	2	0	2	1	0	1	4	2	5	4	2	2	1	0	0	0	3	2	3
T	2	4	0	2	0	2	5	2	4	0	0	1	0	3	1	5	0	0	0	1	0	0	4	0	1	1	0	1	2	2

PWM logo   


 


Evolutionary conservation of regulatory elements    
     Note: Evolutionary conservation of regulatory interactions and promoters is limited to gammaproteobacteria.
TF-target gene evolutionary conservation
Promoter-target gene evolutionary conservation


Evidence    

 [BPP] Binding of purified proteins

 [GEA] Gene expression analysis

 [HIBSCS] Human inference based on similarity to consensus sequences

 [AIBSCS] Automated inference based on similarity to consensus sequences

 [ICWHO] Inferred computationally without human oversight

 [ITCR] Inferred through co-regulation



Reference(s)    

 [1] Hendricks EC., Szerlong H., Hill T., Kuempel P., 2000, Cell division, guillotining of dimer chromosomes and SOS induction in resolution mutants (dif, xerC and xerD) of Escherichia coli., Mol Microbiol 36(4):973-81

 [2] Li C., Wang Y., Chen G., 2013, Interaction investigations of HipA binding to HipB dimer and HipB dimer + DNA complex: a molecular dynamics simulation study., J Mol Recognit 26(11):556-67

 [3] Lin CY., Awano N., Masuda H., Park JH., Inouye M., 2013, Transcriptional Repressor HipB Regulates the Multiple Promoters in Escherichia coli., J Mol Microbiol Biotechnol 23(6):440-447

 [4] Black DS., Irwin B., Moyed HS., 1994, Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis., J Bacteriol 176(13):4081-91

 [5] Maciag A., Peano C., Pietrelli A., Egli T., De Bellis G., Landini P., 2011, In vitro transcription profiling of the σS subunit of bacterial RNA polymerase: re-definition of the σS regulon and identification of σS-specific promoter sequence elements., Nucleic Acids Res 39(13):5338-55

 [6] Black DS., Kelly AJ., Mardis MJ., Moyed HS., 1991, Structure and organization of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis., J Bacteriol 173(18):5732-9

 [7] Rotem E., Loinger A., Ronin I., Levin-Reisman I., Gabay C., Shoresh N., Biham O., Balaban NQ., 2010, Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence., Proc Natl Acad Sci U S A 107(28):12541-6

 [8] Hansen S., Vulic M., Min J., Yen TJ., Schumacher MA., Brennan RG., Lewis K., 2012, Regulation of the Escherichia coli HipBA Toxin-Antitoxin System by Proteolysis., PLoS One 7(6):e39185

 [9] Schumacher MA., Piro KM., Xu W., Hansen S., Lewis K., Brennan RG., 2009, Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB., Science 323(5912):396-401

 [10] Evdokimov A., Voznesensky I., Fennell K., Anderson M., Smith JF., Fisher DA., 2009, New kinase regulation mechanism found in HipBA: a bacterial persistence switch., Acta Crystallogr D Biol Crystallogr 65(Pt 8):875-9

 [11] Schumacher MA., Min J., Link TM., Guan Z., Xu W., Ahn YH., Soderblom EJ., Kurie JM., Evdokimov A., Moseley MA., Lewis K., Brennan RG., 2012, Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance., Cell Rep 2(3):518-25

 [12] Schumacher MA., Balani P., Min J., Chinnam NB., Hansen S., Vulic M., Lewis K., Brennan RG., 2015, HipBA-promoter structures reveal the basis of heritable multidrug tolerance., Nature 524(7563):59-64

 [13] Zhao J., Wang Q., Li M., Heijstra BD., Wang S., Liang Q., Qi Q., 2013, Escherichia coli toxin gene hipA affects biofilm formation and DNA release., Microbiology 159(Pt 3):633-40

 [14] Korch SB., Hill TM., 2006, Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation., J Bacteriol 188(11):3826-36



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