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Keywords:

  • signal transduction;
  • two-component system;
  • histidine kinase;
  • cell envelope stress

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

Two-component signal-transducing systems (TCS) consist of a histidine kinase (HK) that senses a specific environmental stimulus, and a cognate response regulator (RR) that mediates the cellular response. Most HK are membrane-anchored proteins harboring two domains: An extracytoplasmic input and a cytoplasmic transmitter (or kinase) domain, separated by transmembrane helices that are crucial for the intramolecular information flow. In contrast to the cytoplasmic domain, the input domain is highly variable, reflecting the plethora of different signals sensed. Intramembrane-sensing HK (IM-HK) are characterized by their short input domain, consisting solely of two putative transmembane helices. They lack an extracytoplasmic domain, indicative for a sensing process at or from within the membrane interface. Most proteins sharing this domain architecture are found in Firmicutes bacteria. Two major groups can be differentiated based on sequence similarity and genomic context: (1) BceS-like IM-HK that are functionally and genetically linked to ABC transporters, and (2) LiaS-like IM-HK, as part of three-component systems. Most IM-HK sense cell envelope stress, and identified target genes are often involved in maintaining cell envelope integrity, mediating antibiotic resistance, or detoxification processes. Therefore, IM-HK seem to constitute an important mechanism of cell envelope stress response in low G+C Gram-positive bacteria.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

Life in the microbial world is characterized by constant interactions between the bacterial cell and its environment. A prerequisite for survival in a complex habitat is the ability of a bacterium to ‘know’ its state by closely monitoring critical parameters: osmotic activity, ionic strength, composition and concentration of nutrients and presence of harmful compounds are among a plethora of variables that are part of the equation that each cell has solve in order to find the ideal niche to thrive and prosper.

Two-component signal transduction (TCS) is a ubiquitously distributed regulatory principle in bacteria, but can also be found in lower eukaryotes such as fungi, slime molds and plants (Hoch & Silhavy, 1995; Hwang et al., 2002; Inouye & Dutta, 2003). It is a versatile system that allows adaptational response to a huge variety of environmental stimuli, based on a simple modular system: a membrane-bound histidine kinase (HK) that acts as a sensor and a response regulator (RR) that mediates the cellular response, most often by regulating differential gene expression. The activity of, as well as the communication between these two components is mediated by three phospho-transfer reactions: (1) the autophosphorylation of a conserved histidine in the sensor, (2) the phospho-transfer to a conserved aspartate in the RR, and (3) dephosphorylation of the RR to set back the system to the prestimulus state (Parkinson, 1993). With a few exceptions, all bacterial genomes sequenced so far harbor multiple copies of genes encoding TCS. While some systems have been studied in great detail (most notably the paradigms EnvZ/OmpR and CheA/CheY in Escherichia coli), and transcriptome approaches allowed initial genome-wide investigations on TCS, most of these systems are still uncharacterized.

A classification of histidine kinases, based on the H-box of the kinase domain, was proposed by Fabret et al. (1999) and found widespread use. A more comprehensive and detailed sequence analysis, based on all six conserved boxes in the transmitter domain (Grebe & Stock, 1999), allows a more accurate subgrouping of histidine kinases. In contrast, investigations of the input (sensing) domains of histidine kinases are much more difficult, due to the great sequence diversity reflecting the range of different input signals sensed (Hoch, 2000). Comparative genomics analyses – applying sophisticated bioinformatics algorithms – have been performed only recently, resulting in the identification of a number of novel conserved input domains (Anantharaman & Aravind, 2000, 2001, 2003; Galperin et al., 2001a, b; Zhulin et al., 2003; Galperin, 2004). Such analyses are crucial to understand the individual physiological role of a TCS, which is defined by the input domain of HK and the output domain of the RR, rather than the highly conserved transmitter–receiver module, which facilitates the communication between HK and RR. With regard to the amount of data generated by genome sequencing projects, new approaches are necessary to predict the biological function of uncharacterized signal-transducing systems. Here, we present such an alternative approach that is based on domain architecture and genomic context (instead of sequence similarity alone), to identify HK with potential roles in sensing bacterial cell envelope stress response. Our comparative genomics prediction will be evaluated – and is supported – by the published function of some of the corresponding TCS.

Definition and identification of intramembrane-sensing histidine kinases

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

We recently identified three histidine kinases – LiaS, BceS and YvcQ – as part of the cell envelope stress stimulon of Bacillus subtilis (Mascher et al., 2003). These proteins share striking similarities in their overall domain organization: they are small sensor kinases with no more than 400 amino acids total length. The N-terminal sensing domain consists of two deduced transmembrane helices with a spacing of less than 25 amino acids that is therefore buried almost entirely in the cytoplasmic membrane, indicating that no extracellular stimulus is detected (Fig. 1). The cytoplasmic transmitter domain harbors only the standard features characteristic for all HK (HisKA, HATPase_c for kinase activity, and – sometimes – dimerization domains such as HAMP, Fig. 1), but lacks any additional domains that would allow signal detection within the cytoplasm. Therefore, it was proposed that these proteins sense their stimulus either directly inside or at the surface of the cytoplasmic membrane. Accordingly, these proteins were named intramembrane-sensing histidine kinases (IM-HK; Mascher et al., 2003).

image

Figure 1.  Domain organization of intramembrane-sensing histidine kinases. Basic types are shown and compared with EnvZ. Scale bar in amino acids. The figure is based on the graphical output of the SMART web interface (http://smart.embl-heidelberg.de). The protein is represented by the grey line. Blue vertical bars represent putative transmembrane helices. Size and position of conserved domains is indicated by the labeled symbols (HAMP, green pentagon; HisKA, turquoise square; HATPase_c, turquoise triangle). SMART/Pfam accession numbers for the domains are: HAMP (SM00304/PF00672), HATPase_c (SM00387/PF02518), HisKA (SM00388/PF00512, or PF07730 (Pfam:HisKA_3) in case of LiaS-like HK). Abbreviations of bacterial species: Eco, Escherichia coli; Bsu, Bacillus subtilis.

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This review is based on a comprehensive database analysis of IM-HK that included domain organization, genomic context conservation, and sequence homology, in order to define and classify this new subfamily of sensor kinases. For that purpose, the ‘Simple Modular Architecture Research Tool’ SMART (Schultz et al., 1998) (URL: http://smart.embl-heidelberg.de/) and the recently released ‘Microbial Signal Transduction database’ MiST (Ulrich et al., 2005) (URL: http://genomics.ornl.gov/mist/) were screened for histidine protein kinases fulfilling the criteria mentioned above. The resulting dataset was manually analyzed to identify and omit duplicated sequences (i.e. those derived from sequencing more than one strain of a given species). A total of 147 proteins (out of almost 5000 HK in the databases, based on more than 350 completely sequenced microbial genomes with about twice as much under way, as of July 2006) share the domain architecture of IM-HK, as described above. The vast majority of IM-HK are derived from genomes of Gram-positive bacteria, primarily with a low G+C content (110 proteins, with 79 finished genomes in MiST), and some also from Actinobacteria (11 proteins, 24 finished genomes). Only 17 IM-HK can be found in Proteobacteria (171 finished genomes!), and four in Cyanobacteria (Tables 1–3). Two phylogenetically distinct subgroups of IM-HK, found almost exclusively in Firmicutes bacteria, are genetically linked to genes encoding ABC transporters or a conserved transmembrane protein, respectively (Figs 2 and 3). The functional connection between IM-HK and these proteins, and the signal-sensing mechanism of IM-HK will be discussed, based on initial investigations and the available literature.

Table 1.   List of intramembrane-sensing histidine kinases associated with ABC transporters
ProteinAccession no.OrganismPhylumLength*ClassTMRReference
  • *

    Length in amino acids (aa).

  • Assignment is based on the histidine kinase classification system of Grebe & Stock (1999). Some remarks concerning this classification: BacS (Bli) and YbdK (Bsu) lack a G-Box. ‘–’ Some kinases could not be assigned to any of the HK subgroups described so far.

  • Putative transmembrane regions (TMR) were identified by the TMHMM2 algorithm (Krogh et al., 2001).

  • §

    The two proteins from S. agalactiae were listed under a different name in our initial analysis (Mascher et al., 2003). GBS0122 and GBS0964 were later renamed to SAG0124 and SAG0977, respectively.

  • NA, not available.

BceS-like IM-HK
BA5088AAP28764B. anthracisFirmicutes340HPK3i09–26, 37–56Genome sequence
YvcQNP_834144B. cereusFirmicutes360HPK3i12–34, 44–61Genome sequence
YxdKAAP09499B. cereusFirmicutes327HPK3i12–29, 34–56Genome sequence
BC4836AAP11737B. cereusFirmicutes340HPK3i09–26, 37–56Genome sequence
BCE2618NP_978924B. cereusFirmicutes334HPK3i17–36, 41–63Genome sequence
BCE4530NP_980823B. cereusFirmicutes369HPK3i21–43, 53–71Genome sequence
ABC0255YP_173759B. clausiiFirmicutes345HPK3i17–36, 41–63Genome sequence
ABC3228YP_176723B. clausiiFirmicutes350HPK3i12–34, 38–60Genome sequence
BH3912BAB07631B. haloduransFirmicutes334HPK3i12–29, 33–55Genome sequence
BH2700BAB06419B. haloduransFirmicutes343HPK3i13–35, 41–63Genome sequence
BH0754BAB04473B. haloduransFirmicutes353HPK3i13–32, 42–64Genome sequence
BH0289BAB04008B. haloduransFirmicutes346HPK3i12–34, 44–63Genome sequence
BH0272BAB03991B. haloduransFirmicutes331HPK3i09–26, 36–53Genome sequence
YtsBAAU43025B. licheniformisFirmicutes334HPK3i12–29, 33–55Genome sequence
YxdKAAU42958B. licheniformisFirmicutes326HPK3i07–29, 34–53Genome sequence
BLi04270AAU43083B. licheniformisFirmicutes335HPK3i09–28, 38–57Genome sequence
BE01181NAB. stearothermoph.Firmicutes334HPK3i12–29, 33–55Genome sequence
BceSCAB15017B. subtilisFirmicutes334HPK3i12–29, 33–55(Ohki et al., 2003)
YvcQCAB15476B. subtilisFirmicutes356HPK3i10–32, 44–63(Joseph et al., 2002)
YxdKCAB16001B. subtilisFirmicutes325HPK3i07–29, 34–56(Joseph et al., 2004)
BT9727_2379YP_036705B. thuringiensisFirmicutes334HPK3i17–36, 41–63Genome sequence
BT9727_4172YP_038489B. thuringiensisFirmicutes370HPK3i21–43, 53–71Genome sequence
BT9727_4568YP_038880B. thuringiensisFirmicutes340HPK3i09–26, 37–56Genome sequence
CAC1517AAK79484C. acetobutylicumFirmicutes349HPK3i12–34, 39–61Genome sequence
CAC0372AAK78352C. acetobutylicumFirmicutes334HPK3i15–34, 41–60Genome sequence
CAC0225AAK78206C. acetobutylicumFirmicutes339HPK3i13–30, 40–62Genome sequence
CB03066NAC. botulinumFirmicutes352HPK3i15–37, 42–64Genome sequence
CB03117NAC. botulinumFirmicutes326HPK3i12–34, 38–57Genome sequence
DF02597NAC. difficileFirmicutes334HPK3i13–30, 40–61Genome sequence
CPE0120BAB79826C. perfringensFirmicutes337HPK3i12–31, 36–55Genome sequence
CPE0841BAB80547C. perfringensFirmicutes336HPK3i12–31, 36–58Genome sequence
CTC00393AAO35029C. tetaniFirmicutes352HPK3i15–37, 42–64Genome sequence
CTP22AAO37418C. tetaniFirmicutes314HPK3i02–16, 26–48Genome sequence
DSY0573YP_516806D. hafnienseFirmicutes331HPK3i15–32, 39–61Genome sequence
DSY3679YP_519912D. hafnienseFirmicutes328HPK3i20–37, 42–59Genome sequence
EF0927AAO80735E. faecalisFirmicutes341HPK3i13–30, 40–62(Teng et al., 2002)
EFA03839NAE faeciumFirmicutes341HPK3i13–30, 40–62Genome sequence
GK2341YP_148194G. kaustophilusFirmicutes334HPK3i12–29, 33–55Genome sequence
LsaHPK1AAD10259L. sakeiFirmicutes339HPK3i12–30, 40–62Genome sequence
LlaKinGAAK05844L. lactisFirmicutes291HPK3i13–32, 36–58Genome sequence
LIN1852CAC97083L. innocuaFirmicutes346HPK3i12–30, 40–62Genome sequence
LMO1741CAC99819L. monocytogenesFirmicutes346HPK3i12–30, 40–62Genome sequence
OB0832BAC12788O. iheyensisFirmicutes334HPK3i12–34, 38–55Genome sequence
SA2417BAB58786S. aureusFirmicutes295HPK3i13–30, 35–57Genome sequence
SA0615BAB94487S. aureusFirmicutes346HPK3i17–34, 44–63Genome sequence
SE2194AAO05836S. epidermidisFirmicutes298HPK3i13–32, 36–54Genome sequence
SE0428AAO04025S. epidermidisFirmicutes346HPK3i15–34, 41–63Genome sequence
SH0405YP_252320S. haemolyticusFirmicutes298HPK3i13–30, 34–56Genome sequence
SH2234YP_254149S. haemolyticusFirmicutes344HPK3i15–34, 41–63Genome sequence
SEQ00482NAS. equiFirmicutes325HPK3i09–31, 35–57Genome sequence
SAG0977§AAM99860S. agalactiaeFirmicutes312HPK3i10–32, 37–56Genome sequence
MbrDBAB83946S. mutansFirmicutes317HPK3i12–31, 35–57(Tsuda et al., 2002)
str1335(hk07)YP_141691S. thermophilusFirmicutes324HPK3i18–36, 45–63Genome sequence
STH3213YP_077039S. thermophilumActinobact.371HPK3i14–35, 41–61Genome sequence
TDE0656NP_971269T. denticolaSpirochaet.357HPK3i23–42, 55–73Genome sequence
Additional IM-HK associated with ABC transporters
BAS0272YP_026553B. anthracisFirmicutes340 09–26, 31–48Genome sequence
BCZK0257YP_081868B. cereusFirmicutes34010–25, 32–54Genome sequence
BCZK1773YP_083368B. cereusFirmicutes347HPK1b13–35, 45–67Genome sequence
ABC3642YP_177136B. clausiiFirmicutes372HPK2a07–29, 49–71Genome sequence
BacSAAD21212B. licheniformisFirmicutes34810–27, 32–54(Neumüller et al., 2001)
SubSABB80127B. subtilisFirmicutes34710–28, 36–54(Wu et al., 2006)
BT9727_0254YP_034606B. thuringiensisFirmicutes34009–26, 31–48Genome sequence
CAC3516AAK81442C. acetobutylicumFirmicutes350HPK1a07–29, 49–71Genome sequence
CTC01716AAO36431C. tetaniFirmicutes33920–37, 41–60Genome sequence
GK0907YP_146760G. kaustophilusFirmicutes354HPK1b07–29, 49–71Genome sequence
OB0358NP_691279O. iheyensisFirmicutes33307–29, 33–50Genome sequence
SAG0124§AAM99032S. agalactiaeFirmicutes356HPK1b13–35, 50–72Genome sequence
ALR3155BAB74854Anabaena sp.Cyanobact.344HPK1a29–51, 56–78Genome sequence
SLL1590Tr|P73865Synechocystis sp.Cyanobact.350HPK1a29–47, 52–71Genome sequence
NPU03400NAN. punctiformeCyanobact.367HPK1a21–43, 63–85Genome sequence
Table 2.   List of LiaS-like intramembrane-sensing histidine kinases
ProteinAccession no.OrganismPhylumLength*ClassTMRReference
  • *

    Length in amino acids (aa).

  • Assignment is based on the histidine kinase classification system of Grebe & Stock (1999).

  • Putative transmembrane regions (TMR) were identified by the TMHMM2 algorithm (Krogh et al., 2001).

  • §

    A liaG homolog is only present in B. subtilis, B. licheniformis and B. halodurans. In the two Listeria species, the liaIH homologs form an independent transcriptional unit, but are predicted to be under control of LiaR-homologous response regulators (Jordan et al., 2006).

  • NA, not available.

Genomic context liaIH(G)FSR-like§
BA1456AAP25398B. anthracisFirmicutes351HPK710–32, 53–75Genome sequence
YvqEAAP08419B. cereusFirmicutes351HPK710–32, 53–75Genome sequence
ABC3375YP_176869B. clausiiFirmicutes354HPK707–29, 49–71genome sequence
BH1199BAB04918B. haloduransFirmicutes351HPK712–34, 49–71Genome sequence
YvqEAAU24951B. licheniformisFirmicutes353HPK713–35, 50–72Genome sequence
BE02643NAB. stearothermoph.Firmicutes344HPK705–27, 42–64Genome sequence
LiaSCAB15299B. subtilisFirmicutes360HPK713–35, 50–72(Mascher et al., 2004)
BT9727_1321YP_035655B. thuringiensisFirmicutes351HPK710–32, 53–75Genome sequence
LIN1020CAC96251L. innocuaFirmicutes352HPK707–29, 49–71Genome sequence
LMO1021CAC99099L. monocytogenesFirmicutes352HPK707–29, 49–71Genome sequence
OB2823BAC14779O. iheyensisFirmicutes350HPK707–29, 52–74Genome sequence
Genomic context liaFSR-like
EF2912AAO82600E. faecalisFirmicutes367HPK709–31, 51–73Genome sequence
KinDAAG53722L. lactisFirmicutes332HPK705–27, 50–72(O'Connell-Motherway et al., 2000)
LSA1370YP_395981L. sakeiFirmicutes354HPK707–29, 52–77Genome sequence
OB1161BAC13117O. iheyensisFirmicutes356HPK716–38, 48–70Genome sequence
VraSCAG40962S. aureusFirmicutes347HPK713–35, 45–67(Kuroda et al., 2003)
SE1570NP_765125S. epidermidisFirmicutes348HPK713–35, 45–67Genome sequence
SH1070YP_252985S. haemolyticusFirmicutes348HPK713–35, 45–67Genome sequence
SSP0908YP_300998S. saprophyticusFirmicutes347HPK707–25, 43–69Genome sequence
SAG0321CAD45954S. agalactiaeFirmicutes339HPK707–29, 47–69Genome sequence
SEQ00811NAS. equiFirmicutes334HPK707–25, 45–67Genome sequence
SMU.486NP_720926S. mutansFirmicutes334HPK707–25, 45–67Genome sequence
HK03(spr0343)AAK74553S. pneumoniaeFirmicutes331HPK707–25, 45–67(Lange et al., 1999)
SPy1622NP_269673S. pyogenesFirmicutes334HPK707–25, 45–67Genome sequence
str1421YP_141773S. thermophilusFirmicutes336HPK705–25, 45–64Genome sequence
Table 3.   Miscellaneous intramembrane-sensing histidine kinases
ProteinAccession no.OrganismPhylumLength*ClassTMRReference
  • *

    Length in amino acids (aa).

  • Assignment is based on the histidine kinase classification system of Grebe & Stock (1999). Some remarks concerning this classification: In SCO6424, the phosphoryl-accepting histidine residue is replaced by a tyrosine residue. The D/F-Box is only weakly conserved in BL1001 (Blo), SCO3740 and SCO6163. YbdK (Bsu) lacks a G-Box. ‘–’ Some HK could not be assigned to any of the HK subgroups described so far.

  • Putative transmembrane regions (TMR) were identified by the TMHMM2 algorithm (Krogh et al., 2001).

  • §

    Our initial analysis (Mascher et al., 2003) contained one additional IM-HK, ArcB from Haemophilus influenzae, which was based on the published genome sequence. We later noticed that this protein, HI0220, was a sequencing artifact of the full-length ArcB protein (Manukhov et al., 2000) and does not belong to the IM-HK. Two proteins were listed under a different name: GBS0430 was renamed SAG0394 after completion of the genome sequence. A second IM-HK from Thermotoga maritima was originally mis-labeled as TM1258 and is listed here with its correct protein ID, TM0127.

IM-HK associated with multidrug-efflux pumps
Bcep_A4348YP_368588Burkholderia sp.Proteobacteria330HPK2b13–35, 50–72Genome sequence
Bcep_B3051YP_373805Burkholderia sp.Proteobacteria361HPK2a15–37, 56–78Genome sequence
Bcep_C6826YP_366516Burkholderia sp.Proteobacteria379HPK2a15–37, 56–78Genome sequence
RS05453CAD17466R. solanacearumProteobacteria360HPK2a19–41, 56–78Genome sequence
RPA2367CAE27808R. palustrisProteobacteria367HPK2a16–38, 53–75Genome sequence
RS03089CAD18605R. solanacearumProteobacteria365HPK2b13–35, 45–67Genome sequence
Rru_A2930YP_428014R. rubrumProteobacteria352HPK1a21–43, 58–80Genome sequence
IM-HK without genomic context conservation
BA1956AAP25850B. anthracisFirmicutes351HPK1b13–35, 45–67Genome sequence
BA3066AAT32182B. anthracisFirmicutes33315–37, 49–71Genome sequence
GtcSCAA55265B. brevisFirmicutes37005–22, 42–64(Turgay & Marahiel, 1995)
BC1957AAP08928B. cereusFirmicutes348HPK1b07–29, 44–66Genome sequence
BC1801AAP08775B. cereusFirmicutes35813–35, 50–67Genome sequence
BC3042NP_832788B. cereusFirmicutes33115–37, 49–71Genome sequence
BH1809BAB05528B. haloduransFirmicutes351HPK2a04–26, 47–66Genome sequence
YbdKCAB11995B. subtilisFirmicutes32003–25, 40–62(Fabret et al., 1999)
BT9727_1791YP_036123B. thuringiensisFirmicutes351HPK1b13–35, 45–67Genome sequence
BT9727_2824YP_037148B. thuringiensisFirmicutes33115–37, 49–71Genome sequence
CAC0831AAK78807C. acetobutylicumFirmicutes366HPK2b13–34, 63–80Genome sequence
DSY2529YP_518762D. hafnienseFirmicutes282HPK5?09–31, 41–62Genome sequence
Moth_1622YP_430467M. thermoaceticaFirmicutes275HPK5?07–26, 36–58Genome sequence
SaeSAAD48403S. aureusFirmicutes353HPK2a09–31, 41–63(Giraudo et al., 1997)
SE0121AAO03718S. epidermidisFirmicutes36313–35, 55–77Genome sequence
SH0335YP_252250S. haemolyticusFirmicutes33213–35, 55–77Genome sequence
SAG0394§AAM99300S. agalactiaeFirmicutes345HPK1a07–26, 36–58Genome sequence
HK08CAB54579S. pneumoniaeFirmicutes350HPK1a15–37, 42–64(Lange et al., 1999)
HK01CAB54567S. pneumoniaeFirmicutes324HPK3i07–26, 36–58(Lange et al., 1999)
TTE0562NP_622234T. tengongensisFirmicutes289HPK5?08–29, 42–62Genome sequence
BL1001AAN24809B. longumActinobacteria358HPK1a32–51, 53–75Genome sequence
SAV2971BAC70682S. avermitidisActinobacteria368HPK1a28–47, 54–76Genome sequence
SAV7391BAC75102S. avermitidisActinobacteria388HPK753–74, 84–106Genome sequence
SCO3740CAB76987S. coelicolorActinobacteria370HPK1a05–27, 40–62(Hutchings et al., 2004)
SCO5282CAC04497S. coelicolorActinobacteria375HPK1a35–54, 61–83(Hutchings et al., 2004)
SCO6424CAA18911S. coelicolorActinobacteria331HPK712–31, 46–68(Hutchings et al., 2004)
SCO5784CAA18321S. coelicolorActinobacteria358HPK734–56, 69–91(Hutchings et al., 2004)
SCO6163CAA22397S. coelicolorActinobacteria303HPK1a05–27, 40–62(Hutchings et al., 2004)
STH920YP_074749S. thermophilumActinobacteria346HPK717–40, 51–69Genome sequence
STH2729YP_076558S. thermophilumActinobacteria368HPK717–40, 49–67Genome sequence
Adeh_0410YP_463623A. dehalogenansProteobacteria351HPK2a10–32, 53–75Genome sequence
Bd3450NP_970185B. bacteriovorusProteobacteria29113–35, 55–77Genome sequence
BLL3558BAC48823B. japonicumProteobacteria366HPK2a13–35, 55–77Genome sequence
BLL7277BAC52542B. japonicumProteobacteria363HPK2a12–34, 58–80Genome sequence
Bcen_5050YP_624898B. cenocepaciaProteobacteria361HPK2a10–32, 56–75Genome sequence
Rfer_3574YP_524809R. ferrireducensProteobacteria34213–35, 50–72Genome sequence
Rru_A1884YP_426971R. rubrumProteobacteria34613–35, 55–74Genome sequence
VF0524YP_203907V. fischeriProteobacteria32013–33, 40–59Genome sequence
WS2200CAE11190W. succinogenesProteobacteria29812–31, 41–63Genome sequence
EnvZAAB36612X. nematophilaProteobacteria342HPK2b17–39, 49–71(Tabatabai & Forst, 1995)
Acid345_4169YP_593243acidobacteriumAcidobacteria302HPK2a11–36, 41–66Genome sequence
CYB_0712YP_476959Synechococcus sp.Cyanobacteria353HPK2a24–46, 56–78Genome sequence
Dgeo_1625YP_605089D. geothermalisDeinococci357HPK2a18–37, 48–71Genome sequence
RB11668NP_870094Pirellula sp.Planctomycetes317HPK5?13–35, 39–56Genome sequence
TM0127§NP_227943T. maritimaThermotogae28506–22, 31–50Genome sequence
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Figure 2.  Phylogenetic tree of intramembrane-sensing histidine kinases. The tree was generated using ClustalW and Phylip algorithms, implemented into the BioEdit sequence alignment tool (Hall, 1999). The different groups of IM-HK are highlighted: LiaS-like (light blue), IM-HK associated with ABC transporters (green), IM-HK located next to multidrug-efflux pumps (orange). Orphan HK are underlined. Proteins derived from Firmicutes bacteria are indicated by black lines and text color, non-Firmicutes proteins are given in grey. HK that have been characterized in more detail and are referred to in the text are shown with large and bold letters. For reasons of clarity, not all IM-HK from Tables 1–3 are represented in this figure. In case of high sequence similarity (i.e. orthologous IM-HK from Bacillus anthracis, Bacillus cereus and Bacillus thuringiensis), only one protein is shown (the rest is not shown): BA1456 (BT9727_1321, BceYvqE), BA3066 (BC3042, BT9727_2824), BA1956 (BT9727_1791, BCZK1773, BC1957), BA5088 (BT9727_4568, BC4836), BCE2618 (BT9727_2379), BceYvcQ (BCE4530, BT9727_4172), Bcen_5050 (Bcep18194_B3051), BCZK0257 (BT9727_0254), BH0289 (ABC0255), CTC00393 (CB03066), DSY0573 (DHA03376), EF0927 (EFA03839), LMO1021 (Lin1020), LMO1741 (Lin1852), RPA2367 (BLL3558, RPC_2736), RPB_0413 (RPD_0407), SauVraS (SE1570, SH1070, SSP0908), SA0615 (SE0428, SH2234), SCO3740 (SCO6163), SCO5282 (SAV2971), SCO5784 (SAV7391), Spy1622 (SEQ00811), See Table 1–3 for protein descriptions and details. Abbreviations of bacterial species: Bbr, B. brevis; Bce, B. cereus; Bha, B. halodurans; Bli, B. licheniformis; Bsu, B. subtilis; Sau, S. aureus; Smu, S. mutans; Xne, X. nematophilus.

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Figure 3.  Genomic context, membrane topology and working model of (a) BceS-, and (b) LiaS-like IM-HK. The loci are drawn to scale, with the lines each corresponding to 7 kb. The genes are labeled differently for clarity. Thick-hatched and dotted arrows represent genes coding for histidine kinases and response regulators, respectively. The names of sensory proteins are highlighted. Additional arrow labeling: ABC transporters (white, vertically striped), liaF homologs (black), additional genes within loci (grey), unrelated flanking genes (white). Putative terminators are marked by black vertical bars. (a) Working model for BceS-like IM-HK based on the published work (Joseph et al., 2002; Mascher et al., 2003; Ohki et al., 2003): BceS detects the presence of bacitracin and in turn activates its cognate RR BceR, ultimately resulting in the strong induction of bceAB expression (red arrows). This operon encodes an ABC transporter that then facilitates removal of bacitracin, which therefore no longer acts as an inducer of BceS: the system shuts down again. Note that neither the exact site of bacitracin action nor the mode of its removal by the ABC transporter BceAB are known. A direct interaction of bacitracin with undecaprenol-pyrophosphate has been demonstrated, indicating that it is sensed by BceS either at the inner or outer surface of the cytoplasmic membrane. Origin of the genomic regions (from top to bottom): Bacillus subtilis, Streptococcus mutans, Anabaena sp. (b) Working model for LiaS-like IM-HK: In the absence of cell envelope stress, the LiaRS TCS is kept inactive by LiaF (black T-shaped line). In the presence of envelope stress, LiaS is induced and activates its cognate RR LiaR, which then binds to its target promoters, including its own promoter (positive autoregulatory feedback loop, red arrows). This autoregulation could be demonstrated for B. subtilis LiaRS, S. aureus VraSR, and S. pneumoniae TCS03 (Kuroda et al., 2003; Mascher et al., 2003; Haas et al., 2005). Origin of the genomic regions (from top to bottom): Bacillus subtilis, Enterococcus faecalis. The lia locus from Bacillus species consists of five core genes, homologs to liaIHFSR, whereas only liaFSR-homologous genes encoding the three-component system are conserved in more distantly related cocci. See text and Table 2 for details.

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BceS-like histidine kinases: a two-component system – ABC transporter connection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

The largest distinct group of IM-HK is characterized by a topological link of the corresponding TCS to genes encoding ABC transporters. A total of 70 proteins belong to that subgroup, 65 of which are derived from Gram-positive bacteria with a low G+C content. 55 of these HK (53 from Firmicutes) gather closely in a distinct branch of the phylogenetic tree of IM-HK (Fig. 2). These proteins all belong to the HPK3i subfamily (Table 1). A genetic and functional link between TCS and ABC transporters in the Bacillus/Clostridium group of low G+C Gram-positive bacteria was described and exemplarily verified for three examples from B. subtilis: YvcPQ-YvcRS, YtsAB-YtsCD and YxdJK-YxdLM (Joseph et al., 2002, 2004). In this group of IM-HK, the genes encoding TCS are located next to (mostly upstream of) genes encoding ABC-transporters (Fig. 3a). The latter are organized in a separate operon and are expressed from a promoter that completely depends on the activity of the neighboring TCS. These systems represent tightly regulated detoxification units: The TCS is expressed constitutively and senses the presence of toxic compounds, such as the cell wall antibiotic bacitracin, at sublethal concentrations. Upon induction, the RR specifically activates the expression of the ABC transporter, thereby facilitating removal of the antibiotic (Fig. 3a). Such an inducible resistance mechanism has been demonstrated for BceRS-BceAB and BacRS-BcrABC in case of the bacitracin resistance in B. subtilis and Bacillus licheniformis, respectively (Neumüller et al., 2001; Mascher et al., 2003; Ohki et al., 2003). A homologous system, MbrABCD, has been described in Streptococcus mutans only with regard to bacitracin resistance. No gene expression studies were performed. In this organism, the genes for the TCS are located downstream of the genes encoding the bacitracin exporter (Tsuda et al., 2002), with MbrD encoding the IM-HK (Fig. 3a).

From low G+C Gram-positive bacteria associated with ABC transporters 12 of the 67 IM-HK show significant sequence variations and do not group with the remaining proteins in the phylogenetic tree (Fig. 2 and Table 1). Amongst those are a number of systems that are located next to transporters mediating resistance to cell wall-active nonribosomal peptide antibiotics, such as bacitracin (BacS from B. licheniformis ATCC10716) or subpeptin (SubS from B. subtilis JM4). Both corresponding TCS, BacRS and SubRS, are associated with antibiotic ‘self-resistance’ in these producing strains (Neumüller et al., 2001; Wu et al., 2006). They are homologous to each other and show the same topology as all the other TCS-ABC loci mentioned so far. A functional link between TCS and ABC transporter has been demonstrated in case of BacRS-BcrABC (Neumüller et al., 2001).

The three remaining IM-HK (ALR3155, SLL1590 and NPU03400) were found in the genome sequences of cyanobacteria and share little sequence similarities with the kinases described above. They are closely related to each other but belong to a different subclass of HK (Fig. 2 and Table 1). They also show a different genomic clustering: The genes for the ABC transporter and the TCS are transcribed divergently and share a common intergenic region (Fig. 3a). A regulatory and/or functional link between these TCS and their neighboring ABC transporters has not yet been demonstrated.

LiaS-like histidine kinases: three-component signal transduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

LiaS and its 24 homologs form a phylogenetically clearly distinct group of IM-HK (Fig. 2). They can only be found in Gram-positive bacteria with a low G+C content (Firmicutes). These proteins belong to HPK7, a subclass of histidine kinases that also contains B. subtilis DegS (Msadek et al., 1990) and E. coli NarQ (Chiang et al., 1992).

Most database entries on LiaS-homologs are derived from genome sequencing projects (Table 2). So far, only two members of this subgroup of IM-HK have been described in more detail: the eponymous protein from B. subtilis and VraS from Staphylococcus aureus. The kinases of both TCS sense the presence of cell wall antibiotics (Kuroda et al., 2003; Mascher et al., 2003; Mascher et al., 2004).

The VraSR system responds to the inhibition of cell wall synthesis. It is induced by the presence of diverse cell wall antibiotics such as glycopeptides, β-lactams, bacitracin and d-cycloserine. Transcriptome analysis of VraR-dependent gene expression revealed that this TCS controls a large regulon. The known or assumed functions of some target genes indicate that the VraSR system is involved in coordinating important steps of cell wall biosynthesis (Kuroda et al., 2003; Yin et al., 2006).

In contrast, the biological function of the LiaRS system is still largely unclear, despite significant progress in elucidating its signal transduction mechanism. The LiaRS TCS was originally identified as a component of the regulatory network that orchestrates the cell envelope stress response in B. subtilis (Mascher et al., 2003). It is encoded by the last two genes of the hexa-cistronic liaIHGFSR operon. In the presence of sublethal concentrations of lipid II-interacting antibiotics – such as bacitracin, vancomycin, ramoplanin or nisin – the LiaRS TCS is activated and strongly induces expression of its own locus (positive autoregulatory feedback loop) from a promoter upstream of liaI (PliaI) (Mascher et al., 2004). Additionally, the LiaRS system responds to cationic antimicrobial peptides, alkaline shock, exposure to organic solvents, detergents, ethanol and secrection stress (Petersohn et al., 2001; Wiegert et al., 2001; Hyyryläinen et al., 2005; Pietiäinen et al., 2005). Recently, it was demonstrated that the product of liaF, a gene that is topologically linked to liaSR in the genomes of all species harboring LiaS homologs, is involved in the signal-sensing mechanism of LiaS (Fig. 3b): In a liaF-deletion mutant, the LiaRS system is constitutively ‘ON’, thereby no longer responding to or necessitating a stimulus for full activity. Therefore, LiaF together with LiaRS forms a three-component system (Jordan et al., 2006). LiaF is a conserved membrane anchored protein with an N-terminus consisting of four TMR that is completely buried within the membrane and a cytoplasmic C-terminus crucial for LiaF function (Jordan et al., 2006; S. Jordan and T. Mascher, unpublished observation; see Fig. 3b for details). While an important role of LiaF for signal detection is unquestionable, the biochemical mechanism of the LiaS–LiaF interaction remains to be elucidated. Is LiaF a negative modulator of the intramembrane-sensing mechanism mediated by the IM-HK LiaS – or is it itself the sensor of the LiaF–LiaRS three-component system (due to its membrane topology again necessitating an intramembane signal perception mechanism)? Likewise, the LiaF–LiaS interaction could occur in the membrane interface through the TMR of both proteins or, alternatively, involve the cytoplasmic domain of LiaF and LiaS.

Miscellaneous IM-HK

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

The remaining 52 proteins (Table 3) do not form a defined phylogenetic group, nor do most of them share any other common features. Twenty proteins were identified in genomes of Firmicutes bacteria, 17 in Proteobacteria, and another 10 from Actinobacteria. Again, most of the proteins are found in Gram-positive bacteria (30), but here a significant portion is also derived from Actinobacteria (high G+C). Some of these proteins have been identified as IM-HK in a recent publication on TCS in S. coelicolor (Hutchings et al., 2004). But so far, no further analyses have been carried out on any of the IM-HK from Actinobacteria. Two of the 20 miscellaneous IM-HK from Firmicutes bacteria have been further investigated.

The GtcRS TCS is located adjacent to the grsAB operon of Bacillus brevis. It encodes multienzymes involved in the biosynthesis of the peptide antibiotic gramicidin S (Turgay & Marahiel, 1995). A putative regulatory link between TCS and antibiotic biosynthesis/∼immunity seems indicative, but remains to be demonstrated.

The SaeRS TCS is part of a complex regulatory network that controls the expression of virulence determinants in S. aureus. It transcriptionally activates the production of several exoproteins, such as α- and β-hemolysins and coagulase (Giraudo et al., 1997; Giraudo et al., 1999). The saeRS genes are preceded by a third gene, saeQ, encoding a hydrophobic protein of unknown function (157 amino acid length), directly upstream and partially overlapping with saeR. Further upstream is a forth gene, designated saeP, encoding a cytoplasmic protein of unknown function. The saePQRS locus is expressed from an autoregulated promoter upstream of saeP and is partially terminated by a stem loop, giving rise to a major short transcript saeP and a much weaker full-length transcript saePQRS (Novick & Jiang, 2003; Steinhuber et al., 2003). Organization and expression of this locus is, therefore, somehow reminescent of the lia locus in B. subtilis and its homologs in other bacilli (Mascher et al., 2004; Jordan et al., 2006).

Of the 17 IM-HK from Proteobacteria, seven are located next to putative multidrug-efflux pumps, but a functional connection has not been established so far. Only one of the remaining 10 proteins has been investigated in more detail. EnvZ of Xenorhabdus nematophila is homologous to the ‘classical’ osmo-sensor EnvZ of E. coli in its cytoplasmic C-terminal domain, but lacks its extracytoplasmic domain. While the periplasmic domains have diverged extensively, EnvZ from X. nematophila was still able to complement an ΔenvZ mutant of E. coli. It was shown that EnvZ of X. nematophila was able to sense changes in environmental osmolarity and properly regulate the levels of the cognate response regulator OmpR of E. coli (Tabatabai & Forst, 1995). Therefore, the periplasmic domain of E. coli EnvZ is not necessary for sensing osmolarity. This observation could be viewed as an indication that an unknown number of HK with large extracytoplasmic domains might also be IM-HK. These domains could be obsolete for signal perception, evolutionary remnants whose sole function is to keep the TMR in place for signal perception, as has been suggested before (Hoch, 2000). The EnvZ-OmpR TCS of X. nematophila is involved in the regulation of porine biosynthesis, swarming motility, exoenzyme and antibiotic production (Forst & Boylan, 2002; Kim et al., 2003; Park & Forst, 2006).

Sensor kinases with similarities to IM-HK

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

During our analysis, we noticed two phylogenetically unrelated groups of HK that show striking similarity to LiaS-/BceS-like HK, but do not belong to the group of IM-HK, due to their different mode of signal perception.

VanS proteins of the VanB-type are small sensor kinases that have two putative TMR at the N-terminus with a spacing of 25–30 aa. The corresponding TCS are involved in mediating vancomycin resistance. While there is no sequence conservation in the extracellular spacer between the two TMR, there is recent evidence from VanS of S. coelicolor that these kinases sense vancomycin (and related glycopeptide antibiotics) directly through this short extracellular sensing domain, presumably by binding the drug directly (Hong et al., 2004; Hutchings et al., 2006).

PmrB-BasS-like proteins are also very similar to IM-HK in all respects but their periplasmic spacer between the two TMR, which has a length of 30–35 aa. This short linker contains two highly conserved ExxE motifs that are involved in sensing ferric ions (Wösten et al., 2000). The corresponding TCS mediates resistance to cationic antimicrobial peptides by lowering the overall negative charge of the cell surface through modifications of the lipopolysaccharides (Gunn et al., 1998; Wösten & Groisman, 1999; Gunn et al., 2000).

Both groups of HK – while being involved in responding to cell envelope stress – sense their stimuli directly through the extracytoplasmic spacer between the two TMR, and do therefore not belong to the IM-HK. In this sense, the 25 residue cut-off point used in this study for the extracytoplasmic spacer in IM-HK might indeed be critical.

Conclusions and outlook

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

This review describes a novel subclass of signal-transducing histidine kinases that were identified based on the domain architecture of their sensor domain and the genomic context of the corresponding gene, rather than sequence similarity. The proteins included here share some overall architectural features with regard to domain organization, size of protein and input domain. They are small HK with an overall length of less than 400 amino acids. The N-terminal ‘sensing’ domains of IM-HK consist of two putative membrane-spanning helices separated by no more than 25 amino acids (Tables 1–3).

In our case, the use of the domain organization of the sensing domains (nonconserved by sequence) as a filter criterion has proven a suitable and useful approach that allowed insights into the phylogeny and (putative) function of a novel subgroup of signal-transducing histidine kinases. IM-HK were predominantly found in the phylum Firmicutes (110 out of the 147 proteins listed in Tables 1–3). The two major groups of IM-HK, LiaS- and BceS-like HK, are restricted to Gram-positive bacteria with a low G+C content. One striking feature of these IM-HK is their common physiological role, based on the examples that have already been studied to some extent: they all seem to be involved in sensing cell envelope stress (very often exerted by cell wall active antibiotics) and regulate genes important for cell envelope integrity, detoxification, and virulence. In the light of their phylogenetic distribution, this observation provokes the question, if the mechanism of signal perception for IM-HK is a direct consequence of the difference in cell wall structure between Gram-positive and -negative bacteria. But the most important question – and a big challenge to be addressed experimentally – remains unanswered at the moment: ‘Do so-called intramembrane-sensing histidine kinases sense their stimuli inside the membrane interface?’ This review was written with the hope that it might stimulate further investigations in this direction.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References

This work was supported by grants from the Deutsche Forschungsgemeinschaft (MA 3269/1-1) and the Fonds der Chemischen Industrie. The help of Luke Ulrich with data extraction of IM-HK from the MiST database is gratefully acknowledged. I am indebted to John D. Helmann for invaluable discussions and his continuous support. I would also like to thank Sina Jordan, Tina Wecke and Anna Staroń for critical reading of the manuscript and their helpful comments.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition and identification of intramembrane-sensing histidine kinases
  5. BceS-like histidine kinases: a two-component system – ABC transporter connection
  6. LiaS-like histidine kinases: three-component signal transduction
  7. Miscellaneous IM-HK
  8. Sensor kinases with similarities to IM-HK
  9. Conclusions and outlook
  10. Acknowledgements
  11. References
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