Download Genomic analysis of the histidine kinase family in bacteria and

Microbiology (2001), 147, 1197–1212
Printed in Great Britain
Genomic analysis of the histidine kinase family
in bacteria and archaea
Dong-jin Kim and Steven Forst
Author for correspondence : Steven Forst. Tel : j1 414 229 6373. Fax : j1 414 229 3926.
e-mail : sforst!uwm.edu
Department of Biological
Sciences, PO Box 413,
University of Wisconsin, WI
53201, Milwaukee, USA
Two-component signal transduction systems, consisting of histidine kinase
(HK) sensors and DNA-binding response regulators, allow bacteria and archaea
to respond to diverse environmental stimuli. HKs possess a conserved domain
(H-box region) which contains the site of phosphorylation and an ATP-binding
kinase domain. In this study, a genomic approach was taken to analyse the HK
family in bacteria and archaea. Based on phylogenetic analysis, differences in
the sequence and organization of the H-box and kinase domains, and the
predicted secondary structure of the H-box region, five major HK types were
identified. Of the 336 HKs analysed, 92 % could be assigned to one of the five
major HK types. The Type I HKs were found predominantly in bacteria while
Type II HKs were not prevalent in bacteria but constituted the major type (13
of 15 HKs) in the archaeon Archaeoglobus fulgidus. Type III HKs were generally
more prevalent in Gram-positive bacteria and were the major HK type (14 of 15
HKs) in the archaeon Methanobacterium thermoautotrophicum. Type IV HKs
represented a minor type found in bacteria. The fifth HK type was composed of
the chemosensor HKs, CheA. Several bacterial genomes contained all five HK
types. In contrast, archaeal genomes either contained a specific HK type or
lacked HKs altogether. These findings suggest that the different HK types
originated in bacteria and that specific HK types were acquired in archaea by
horizontal gene transfer.
Keywords : classification scheme, phylogenetic analysis, secondary structure analysis,
horizontal gene transfer
INTRODUCTION
In bacteria and archaea, two-component signal transduction systems (Kofoid & Parkinson, 1988 ; Parkinson
& Kofoid, 1992 ; Forst & Roberts, 1994 ; Hoch &
Silhavy, 1995), also referred to as His–Asp phosphorelay
systems (Egger et al., 1997), mediate adaptive responses
to changes in environmental conditions. A typical twocomponent signal transduction system consists of a
membrane-bound sensor histidine kinase (HK) and a
cognate regulatory protein referred to as a response
regulator (RR). HKs usually function as dimeric proteins
that undergo transautophosphorylation on a conserved
histidine residue in response to specific stimuli (Dutta et
al., 1999). The phosphoryl group is subsequently transferred to an Asp residue in the receiver domain on the
.................................................................................................................................................
Abbreviations : HK, histidine kinase ; RR, response regulator.
RR. Modulation of the phosphorylated state of the RR
controls either expression of target genes or cellular
behaviour, such as swimming motility (Hoch & Silhavy,
1995). Environmental stimuli received by highly divergent sensory input domains provides specificity for
the signal transduction pathway and controls the level of
the phosphorylated state of the RR. Bacteria can possess
more than 30 different two-component signal transduction systems (Mizuno, 1997). Bacteria that possess a
large number of HKs generally are able to adapt to a
broad spectrum of environmental stimuli. While HKs
have also been identified in fungi (Ota & Varshavsky,
1993 ; Loomis et al., 1998), amoeba (Schuster et al.,
1996 ; Chang et al., 1998), Neurospora (Alex et al., 1996)
and Arabidopsis (Chang et al., 1993 ; Suzuki et al., 1998),
the HK content in eukaryotic genomes is much lower
than that found in bacterial genomes.
HKs consist of an ATP-binding kinase domain and the
H-box domain which includes the histidine site of
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HK subtype HK
H-box
X-region
+
(a)
Type IA
IB
IC
Type II
Type III
Type IV
CheA
(b)
Kinase type HK
N
G1
F
G2
G3
Orthodox
Unorthodox
CheA
.................................................................................................................................................................................................................................................................................................................
Fig. 1. For legend see facing page.
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Histidine kinase family
phosphorylation. The kinase domain consists of three
conserved consensus motifs called the N-, G1- and G2boxes, and a fourth, more variable sequence, the F-box
(Kofoid & Parkinson, 1988 ; Stock et al., 1988, 1995). In
most HKs, the kinase domain is directly connected to
the C-terminal side of the H-box domain. In contrast, in
the chemosensor CheA, the H-box (P1 domain) resides
at the N terminus of the protein and is separated from
the kinase domain by the intervening P2 and P3 modules
(Garzon & Parkinson, 1996 ; Robinson & Stock, 1999).
The structures of the H-box domain of the osmosensor,
EnvZ (Tomomori et al., 1999) and the P1 domain of
CheA (Zhou & Dalquihst, 1997) have been determined.
The H-box region of EnvZ consists of a four-helix
bundle structure formed by the dimeric association of
two identical subunits while the P1 domain is a
monomeric four-helix bundle structure. While the structure of H-box domains differ, the structure of the kinase
domains of EnvZ of Escherichia coli (Tanaka et al.,
1998) and CheA of Thermatoga maritima (Bilwes et al.,
1999) were shown to be homologous to each other and
to the ATP-binding domains of DNA gyrase B and Hsp
90. The phosphotransfer reaction can be reconstituted
using liberated H-box and kinase domains (Garzon &
Parkinson, 1996 ; Park et al., 1998), indicating that the
individual domains can be obtained as functionally
intact modules.
Besides the typical two-component organization, multistep His–Asp–His–Asp phosphorelay systems can be
composed of individual phosphotransfer proteins. This
modular organization has been extensively investigated
in the multi-step pathway controlling sporulation in
Bacillus subtilis (Appleby et al., 1996 ; Fabret et al.,
1999 ; Hoch, 1995 ; Perraud et al., 1999). Multistep
phosphotransfer reactions can also occur within a single
HK. These so-called hybrid HKs contain additional
phosphotransfer modules referred to as the D1 receiver
and the HPt phosphotransfer domains that are attached
to the C-terminal side of the kinase domain (Appleby et
al., 1996).
The number of HKs recognized has expanded enormously with the advent of microbial genomic sequencing
projects. The HK superfamily has been classified by
numerous criteria. Recently, Grebe & Stock (1999)
separated the HK family into 11 different subtypes based
on cluster analysis of 348 HKs. In the present study,
the HK families in the completed genomes of 22 bacteria
and 4 archaea was analysed. This genomic analysis
divided the HK family into five major types. The HK
type distribution differed markedly between bacteria
and archaea.
METHODS
Analysis of bacterial and archaeal HK families. The HK
family of each genome was assembled using the gene tables of
the completed genomes listed in TIGR (http :\\www.tigr.org).
Additionally,  analysis using the transmitter domains
(H-box plus kinase domain) of EnvZ, CheA, NarX, YehU and
DcuS as the search sequences was performed. During this
analysis ORFs were retrieved which lacked either H-box or
kinase consensus motifs. Also, proteins such as HipA of E. coli
and SpoIIAB of B. subtilis, which contained kinase domains
but lacked an identifiable H-box domain were retrieved. Only
those proteins that contained both an identifiable H-box and
complete kinase domain were included in the HK gene family.
Alignment of H-box and kinase domains. The transmitter
domains were initially aligned using the multi-sequence
alignment program  version 2.1. Refinement of the
alignments was aided by  search analysis and visual
inspection.
Phylogenetic analysis. A distance dendrogram of each HK
family was constructed using the unweighted pair-group
method with arithmetic means (UPGMA) algorithm. Using
this method, five different HK types were identified in E. coli.
For each genome analysed, a dataset, which included the HKs
from E. coli, was created and subsequently analysed using the
UPMGA method. The assignment of HK types and subtypes
within each genome analysed was accomplished using this
approach.
Secondary structure analysis. The PredictProtein server
(http :\\www.embl-heidelberg.de\predictprotein\predictprotein.html) was used to predict the secondary structure of
the H-box region in each HK retrieved. A predicted secondary
structure was assigned to sequences that possessed a liability
value of greater than 7.
RESULTS
Characterization of the HK family of E. coli K-12
HKs were retrieved using the  server within each
genome listed in the TIGR microbial database. Various
transmitters, which included both the H-box region and
kinase domain, were used as search probes. Retrieved
ORFs containing both an H-box region and a kinase
domain were included in the HK gene family. We
initially analysed the genomes containing large HK
families. The HK family of the completed genomic
sequence of E. coli K-12 (Blattner et al., 1997) was
analysed first since it has been extensively studied and
Fig. 1. Alignment of the H-box region of the HKs of E. coli. H-box consensus sequences are boxed. Bold characters depict
invariable residues and characteristic conserved residues of a given subtype are represented by white letters. The
predicted helix–loop–helix structures are underlined. The helix–loop–helix structure of EnvZ is shown by thick lines above
the EnvZ sequence. ‘ j ’ denotes the position of the conserved positive amino acid residue at the end of helix 2. Proline
residues in the putative loop region are shaded. (b) Alignment of the kinase domain of the HKs of E. coli. The conserved
motifs are enclosed in boxes and shaded. Bold characters depict invariable residues and characteristic conserved residues
of a given subtype are represented by white letters. The number of amino acid residues between motifs are represented
by either a single dot (less than 10 residues), by double dots (10–25 residues) or double open circles (more than 25
residues). Dashes represent deleted residues.
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BasS
YgiY
PhoR
YbcZ
BaeS
RstB
EnvZ
CpxA
KdpD
IA
YedV
CreC
YfhK
BarA
RcsC
TorS
IB
ArcB
EvgS
AtoS
IC
HydH
Type I
NtrB
PhoQ
DcuS
Type II
DpiB
Che A
CheA
NarX
Type III
NarQ
UhpB
YehU
Type IV
B2380
0·1 changes
.................................................................................................................................................................................................................................................................................................................
Fig. 2. Phylogenetic analysis of the HKs of E. coli. Dendrogram of the 29 HKs of E. coli analysed using the UPGMA
algorithm. The alignments shown in Fig. 1(a) and (b) were used in the analysis.
the function of 18 of its HKs are presently known (Egger
et al., 1997).
Twenty-nine HKs were retrieved from the genome of E.
coli. Fig. 1(a) shows the amino acid sequence alignment
of the H-box and X regions and Fig. 1(b) shows the
alignment of the kinase domains. During the 
analysis, proteins which contained phosphorelay subdomains but lacked kinase domains were retrieved. For
example, YojN contains an HPt domain but no
identifiable kinase domain. These types of proteins were
not included in the HK gene family.
Phylogenetic analysis separated the HK gene family into
five major branches (Fig. 2). The analysis reveals that
Type I and II HKs are related to each other while Type
III and IV HKs occupy separate branches. Type I and II
HKs both possess orthodox kinase domains, which
contain the N, G1, F and G2 consensus motifs. Type III
and IV HKs possess so-called unorthodox kinase
domains in which N1 of the N-box motif is either a
glycine (Type III) or a proline (Type IV) residue, the Fbox is absent and the G2 motif is truncated (Fig. 1b).
The conserved glycine residue identified on the Cterminal side of the G2 motif in almost all kinase
domains is referred to as the G3 site. The Type I group
contained the largest number of members (72 %). Within
this group, three separate subtypes could be distinguished. The Type IA group contained 12 HKs, the
Type IB group contained the hybrid HKs and the Type
IC group contained three HKs, including the nitrogen
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Histidine kinase family
Table 1. Characteristic features of HK types
HK type
H-box consensus*
Kinase domain
Mean H to N
distance (aa)
Type I
Type II
Type III
Type IV
CheA
HEhR[P
HE[[N[
REhHD[h[[
PHFh[N[
HShKG[
Orthodox
Orthodox
Unorthodox
Unorthodox
Orthodox
116
96
110
92
325
* The bold H represents the invariable histidine residue in the H-box. Conserved hydrophobic residues
(I, L, V, M) are designated by ‘ h ’.
regulator, NtrB. While PhoQ contained a Type I H-box
motif and an orthodox kinase domain, it did not branch
within the Type IA, IB and IC subgroups.
Each of the five HK types contained a characteristic Hbox motif (Fig. 1a). The H-box of Type I HKs contained
the consensus motif HEhRTPh. Secondary structure
analysis predicted a helix–loop–helix structure (underlined in Fig. 1) in the H-box region. This structure was
shown to exist in the NMR solution structure of EnvZ
(Tomomori et al., 1999). Proline residues were present
in the loop region of numerous HKs and positively
charged residues were found at the end of the X-region.
The H-box motif of the Type II HKs possessed a
conserved asparagine residue at position 5 (the invariant
H residue is defined as position 1) and lacked the
positively charged residue and the proline at positions
4 and 6, respectively. These HKs lacked a predicted
helix–loop–helix structure. The H-box motif of Type III
HKs was characterized by an R-E-L sequence on the Nterminal side of the histidine site of phosphorylation and
lacked the conserved positively charged and proline
residues. A helix–loop–helix structure was predicted in
these molecules. The H-box motif of Type IV HKs
contained a proline residue on the N-terminal side and
the conserved sequence FLFNAL on the C-terminal side
of the histidine site of phosphorylation. Finally, the P1
domain of CheA contained the consensus motif HSIKG
and exists at the N terminus of the protein.
The distance between the conserved histidine residue of
the H-box and the conserved asparagine residue of the
kinase domain (H to N distance) was characteristic for
the different HK subtypes. The mean H to N distance
was approximately 116 residues and 96 residues for the
Type I and II HKs, respectively (Table 1). The mean H
to N distance was 110 residues and 92 residues for the
Type III and IV HKs, respectively. The kinase domain of
CheA was characterized by insertions between the N
and G1 boxes and the G1 and F boxes. The N-box of
CheA contained a histidine residue at the N1 position.
The localization of the H-box at the N terminus of CheA
created an H to N distance of 325 residues (Table 1 ;
Kofoid & Parkinson, 1988). Finally, it has been shown
that 26 of the 29 HKs of E. coli are organized in operons
with cognate RRs (Mizuno, 1997).
HK family of Pseudomonas aeruginosa
To determine whether the five major HK types found in
E. coli were present in other bacteria, a phylogenetic
analysis of HK gene family of Psd. aeruginosa (Stover et
al., 2000) using the UMPGA method was performed
(Fig. 3). Psd. aeruginosa possesses 63 HKs. The five HK
types found in E. coli were also identified in Psd.
aeruginosa. The majority of the family members (86 %)
were Type I HKs, containing typical orthodox kinase
domains and H-box motifs. One cluster within the Type
IA group (PA1396, 1976, 1992, 3271 and 4936) contained
orthodox kinase domains while the H-box motifs
contained a non-polar residue at position 4 and a
glutamine residue at position 5. This clade of HKs
formed a distinct branch within the Type IA group. In
addition, a cluster of HKs in the Type IC group
possessed the consensus H-box motif HDLNQPL in
which the asparagine residue replaced the typical
positively charged residue at position 4 and the glutamine residue at position 5 was highly conserved. Psd.
aeruginosa lacked Type II HKs and possessed four
CheAs. Two HKs, PA3078 and PA4380, could not be
assigned to the defined type, so were categorized as
unclassified. Helix–loop–helix structures were predicted
in the H-box region of the Type I and III HKs and the H
to N distances for each of the HK types were similar to
those found in the different HK types of E. coli. Finally,
the majority of the HKs were found in operons with
cognate RRs.
HK families in bacterial genomes
The HK gene families of bacterial genomes listed as
completed in the TIGR database were characterized
using the cluster analysis approach. We began the
analysis with free-living micro-organisms containing
relatively large genomes.
A total of 44 HKs were identified in the genome of
Vibrio cholerae (Heidelberg et al., 2000), which included
three new proteins (VCA0705, VC0694, VCA0851) not
previously listed in the TIGR gene table. V. cholerae
possessed a large Type I group which included 7 Type
IA, 9 Type IB and 12 Type IC molecules (Table 2). We
noted that a cluster of HKs within the Type IC group
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BaeS
CpxA
PA0930
PA2687
PA3206
RstB
PA1158
PA1798
EnvZ
PA5199
PA3191
PA4102
KdpD
PA1636
PA5484
BasS
YgiY
PA4777
PA0757
PA2480
PhoR
PA5361
YedV
PA4886
YbcZ
PA2810
PA1438
PA2524
CreC
PA0464
YfhK
PA1396
PA1976
PA1992
PA3271
PA4036
BarA
PA0928
PA4112
TorS
PA1611
PA3462
PA2824
PA4982
PA2583
PA3044
PA3946
RcsC
ArcB
EvgS
PA4856
PA3974
PA3078
PA4380
AtoS
HydH
PA4725
PA4398
PA2571
PA2882
PA1336
PA5165
PA4293
PA5512
PA4197
PA4546
PA1243
PA2177
NtrB
PA5124
PA1098
PA4494
PA4117
PhoQ
PA1180
PA2656
DcuS
DpiB
CheA
PA0178
PA1458
PA0413
PA3704
NarX
PA3878
NarQ
UhpB
PA1979
PA0600
YehU
B2380
PA5262
IA
IB
Type I
IC
Type II
Che A
Type III
Type IV
IA
IB
IC
0·1 changes
.................................................................................................................................................................................................................................................................................................................
Fig. 3. Phylogenetic analysis of the HKs of Psd. aeruginosa. Dendrogram showing the analysis of a combined dataset of E.
coli and Psd. aeruginosa HKs. HKs of Psd. aeruginosa are represented by bold type.
possessed the H-box motif HDLNNP in which the
typical positively charged residue at position 4 was
substituted by an asparagine residue. The Type I HKs
possessed helix–loop–helix structures in the H-box
region and a mean H to N distance of 110 residues. Type
II, III, IV and CheA HKs were also present in V.
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Histidine kinase family
Table 2. Distribution of HK types in bacteria
HK type
Type I A
Type I B
Type I C
Type II
Type III
Type IV
CheA
Unclassified
Total HKs
Total
proteins
Percentage
HKs
Escherichia
coli
Vibrio
cholerae
12
5
3
2
3
2
1
–
29*
4228
7
9
12
3
3
2
3
4
44*
3885
0n69
1n13
Pseudomonas Xylella
aeruginosa fastidiosa
24
11
16
–
3
1
4
2
63*
5570
1n13
4
1
3
–
–
1
1
1
12*
2904
0n41
Bacillus
subtilis
6
0
5
4
9
3
1
8
36
4100
0n87
Synechocystis Deinococcus Thermotoga Aquifex
sp.
radiodurans maritima aeolicus
11
19
–
–
2
–
2
4
38
4594
0n82
13
2
–
–
4
–
–
1
20
3187
0n62
4
–
1
–
–
–
1
2
8
877
0n43
–
–
–
–
–
–
–
3
3
1512
0n20
* Includes PhoQ-like HK.
cholerae. Additionally, four HKs did not cluster with a
defined group and were therefore placed in an unclassified category. Twenty-eight of the HKs were found on
the large chromosome of V. cholerae (2n96 Mb) while 16
were found on the small chromosome (1n07 Mb). The
majority of the HKs existed in operons with cognate
RRs.
Xylella fastidiosa (Simson, 2000), like E. coli and V.
cholerae, is a member of the γ-subclass of the Proteobacteria. X. fastidiosa contained predominantly Type I
HKs (Table 2) and lacked Type II and III HKs. The HKs
in this bacterium existed in operons with cognate RRs.
The HK family of the Gram-positive bacterium B.
subtilis (Kunst, 1997) contained all five HK types. The
Type I group, containing six Type IA, five Type IC HKs
and no Type IB HKs, was not as large as that found in
the Gram-negative bacteria analysed above, while 25 %
of the HKs belonged to the Type III group. B. subtilis
contained a relatively large number of HKs which did
not cluster within the five defined HK types. Three
unclassified HKs (YtsB, YvcQ, YxdK) clustered together
into one clade while three other unclassified HKs (YbdK,
YrkQ, YccG) formed a separate clade (see Table 5). All
of the HKs of B. subtilis existed in operons with cognate
RR with the exception of the Type IC group which were
orphans (Fabret et al., 1999).
A markedly different HK distribution was found in the
cyanobacterium, Synechocystis sp. (Kaneko et al., 1996).
This bacterium possessed a large Type IB group but
lacked Type IC HKs. Several of the Type IB HKs did not
contain D1 or HPt modules. Whether these Type IB
molecules represent HKs to which additional phosphorelay modules had not been added or are hybrid types
which lost the phosphorelay modules, remains to be
determined. Interestingly, the two CheA proteins identified in Synechocystis sp. contained additional phosphorelay modules (Mizuno et al., 1996). Synechocystis sp.
contains two type III HKs, slr0331 and slr1212. While
slr0331 was a typical Type III HK, slr1212 contained an
atypical H-box sequence (HHRhKNNLQ) connected to
a typical unorthodox kinase domain. Type II and IV
HKs were not present in Synechocystis sp. Finally, only
13 of the HKs were organized in operons with cognate
RRs (Mizuno et al., 1996).
The Gram-positive bacterium Deinococcus radiodurans
(White et al., 1999) contained 20 HKs, 13 of which
belonged to the Type IA group. The HK content of Type
III HKs (4 out of 20) was relatively high. The genome of
this bacterium possesses two chromosomes (2n6 and
0n41 Mb), a megaplasmid (0n18 Mb) and a small plasmid
(45 kb). Thirteen of the HKs were present on the large
chromosome, three were located on the smaller
chromosome and four were located on the megaplasmid.
In the thermophilic bacterium Thermatoga maritima
(Nelson et al., 1999) the majority of the HKs (5 out of 8)
belonged to the Type I group while two HKs remained
unclassified. Seven of the eight HKs of T. maritima
existed in operons with cognate RRs. Finally, the
hyperthermophilic bacterium, Aquifex aeolicus, which
is considered to be one of the earliest diverging
eubacteria (Deckert et al., 1998), possessed three HKs,
none of which could be classified. This organism is
motile and possesses polytrichous flagella but does not
contain an identifiable CheA protein.
In summary, 92 % of the HKs analysed were able to be
assigned to one of the five major HK types. Several
bacteria contained all five HK types. The majority of
HKs (63 %) belonged to the Type I group while the
distribution of the various subtypes varied considerably.
In the bacteria, most of the HKs were organized in
operons with cognate RRs, with the notable exception
of Synechocystis.
HK families of human pathogens
The size of the genomes of pathogenic bacteria is
generally smaller than that of free-living bacteria (Table
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Table 3. Distribution of HK types in pathogenic bacteria
HK type
Haemo- Neisseria Rickettsia
philus meningi- prowazekii
tidis
influenzae
MC58
Type I A
2
Type I B
1
Type I C
–
Type II
–
Type III
1
Type IV
–
CheA
–
Unclassified
–
Total HKs
4
Total proteins 1730
Percentage
0n23
HKs
HK subtype
2
–
1
–
1
–
–
1
5
2158
0n23
HK
1
2
1
–
–
–
–
–
4
834
0n48
Helicobacter
pylori
–
–
1
–
–
–
1
2
4
1590
0n25
Campylo- Chlamydo- Chlamydia Borrelia Treponema Mycotracho- burgdorferi pallidum bacterium
phila
bacter
tuberculosis
jejuni pneumoniae matis
CWL029 serovar D
–
–
1
–
–
–
1
5
7
1654
0n42
–
–
1
–
–
–
–
–
1
1073
0n09
–
–
1
–
–
–
–
–
1
894
0n11
–
1
1
–
–
–
2
–
4
1283
0n31
9
–
–
–
4
–
–
–
13
3924
0n33
–
–
1
–
–
–
1
–
2
1041
0n19
H-box
(a)
+
Type I
Type II
CheA
Kinase type
(b)
HK
N
G1
F
G2
G3
Orthodox
CheA
.................................................................................................................................................................................................................................................................................................................
Fig. 4. Alignment of the kinase and H-box regions of Arc. fulgidus. (a) Sequence alignment of the H-box regions.
Shadings and symbols are as in Fig. 1. Only AF1483 and CheA possessed predicted helix–loop–helix structures. (b)
Sequence alignment of the kinase domains.
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Histidine kinase family
BaeS
BasS
YgiY
PhoR
YbcZ
CpxA
RstB
EnvZ
KdpD
YedV
CreC
YfhK
AtoS
HydH
NtrB
BarA
RcsC
TorS
ArcB
EvgS
AF1483
mth444
PhoQ
DcuS
DpiB
AF1721
AF1639
AF1515
AF0021
AF0208
AF0893
784830
AF0450
AF0770
AF1467
AF2109
AF1184
AF1452
CheA
AF1040
NarX
NarQ
UhpB
mth292
mth356
mth619
mth174
mth468
mth446
mth560
mth823
mth985
mth123
mth1124
mth459
mth901
mth902
YehU
B2380
IA
IC
Type I
IB
Type II
Type III
Type IV
0·1 changes
.................................................................................................................................................................................................................................................................................................................
Fig. 5. Phylogenetic analysis of the HKs of Arc. fulgidus and Mbc. thermoautotrophicum. Dendrogram showing the
analysis of a combined dataset of HKs of E. coli, Arc. fulgidus and Mbc. thermoautotrophicum. HKs of Arc. fulgidus and
Mbc. thermoautotrophicum are represented by bold type.
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D. -j. K I M a n d S. F O R S T
Table 4. Distribution of HK types in archaea
HK type
Type I A
Type I B
Type I C
Type II
Type III
Type IV
CheA
Total HKs
Total proteins
Percentage HKs
Methanobacterium
thermoautotrophicum
Archaeoglobus
fulgidus
Pyrococcus
horikoshii
–
1
–
–
14
–
–
15
1855
0n80
–
1
–
13
–
–
1
15
2436
0n61
–
–
–
–
–
–
1
1
2061
0n04
3). The mean HK content of the pathogenic bacteria
was 0n26 % as compared with 0n65 % for the free-living
bacteria. The human pathogenic bacteria contained
predominantly Type I HKs (Table 3). Interestingly, the
Gram-positive bacterium, Mycobacterium tuberculosis
(Davies et al., 1998) contained a relatively high content
(4 of 13) of Type III HKs. One of the Type III HKs,
Rv3220, contained a typical unorthodox kinase domain
and the atypical H-box sequence HHRhKNNLQ which
was similar to the H-box of slr1212 of Synechocystis sp.
These proteins are referred to as Type IIIB HKs (see
Table 5). The majority of the HKs and RRs in these
bacteria were organized in operons with cognate RRs.
Helicobacter pylori and Campylobacter jejuni, both of
which belong to the δ-subclass of the Proteobacteria,
contained several unclassified HKs. This finding suggests
that this group of bacteria may possess a unique HK
type that is not yet identified in the current HK dataset.
Analysis of the HK family of archaeal genomes
The amino acid sequence alignment of the H-box
regions and kinase domains of the 15 HKs of
Archaeoglobus fulgidus (Klenk et al., 1998) is shown in
Fig. 4(a) and (b), respectively. Thirteen of the HKs
belonged to the Type II subtype while only one belonged
to the Type I group. The H-box module of Type II HKs
contained the characteristic asparagine residue at
position 5. The H-box of the Type II HKs lacked a
predictable secondary structure. Highly conserved glutamic acid and positively charged residues were
identified downstream of the H-box (shaded in Fig. 4a).
The kinase domains (Fig. 4b) possessed a conserved
glycine residue in the F-box and the mean H to N
distance was 96 residues. Cluster analysis revealed that
the Type II group of Archaeoglobus formed a separate
clade, designated the IIB subtype, within the Type II
group of E. coli (Fig. 5). The 13 HKs did not exist in
operons with the nine RRs identified in Archaeoglobus.
Earlier analysis of the Methanobacterium thermoautotrophicum genome identified 15 HKs (Smith et al., 1997).
The H-box region of 14 of these HKs contained the
Methanococcus
jannaschii
–
–
–
–
–
–
–
0
1738
0
Aeropyrum
pernix
–
–
–
–
–
–
–
0
2694
0
motif HHRVKNNLQ which was identical to the H-box
sequence found in Mycobacterium and Synechocystis.
HKs containing this sequence belong to the Type IIIB
group. Cluster analysis also showed that the HKs of
Mbc. thermoautotrophicum branched within the Type
III group forming a clade that was distinct from the E.
coli group (Fig. 5). The mean H to N distance of the
Mbc. thermoautotrophicum HKs was 110 residues.
Mbc. thermoautotrophicum possessed one orthodox
HK subtype and did not contain semi-orthodox, minor,
CheA, tripartite or hybrid HKs. Finally, most of the
HKs were not organized in operons with cognate RRs.
Methanococcus jannaschii (Bult et al., 1996) and
Aeropyrum pernix (Kawarabayasi et al., 1999) were
previously found to lack HKs. A re-examination of these
genomes confirmed that HKs were missing in these
organisms. The genome of Pyrococcus horikoshii has
been completed recently (Kawarabayasi et al., 1998).
The only HK found in this genome was CheA (Table 4).
The HK and RR organization in archaea was markedly
different than that found in bacteria. Most of the HKs in
Arc. fulgidus and Mbc. thermoautotrophicum were not
organized in operons with a cognate RR. Only AF0450
of Arc. fulgidus and MTH0902 and MTH0444 of Mbc.
thermoautotrophicum (Smith et al., 1997) were located
in operons with a cognate RR.
The genome sequence of the archaeon Halobacterium
sp. was recently completed (Ng et al., 2000). Of the 14
reported HKs, we retrieved 12 HKs, 8 of which formed
a clade within the Type I group but were distinct from
the IA, IB and IC subtypes. These HKs appear to
represent a subtype that is so far unique to Halobacterium. Three Type II HKs and one CheA were also
identified. Finally, as found in Archaeoglobus, there
were more HKs (14) than RRs (6) in Halobacterium.
DISCUSSION
Phylogenetic analysis of HKs in numerous bacterial and
archaeal genomes led to the identification of five major
HK types. Of the 336 HKs analysed in this study 92 %
could be assigned to one of the five HK types. Type I and
II HKs possessed orthodox kinase domains while Type
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Histidine kinase family
Table 5. Classification of HK family of completed genomes
Genome
Type I
IA
Escherichia coli
K-12
Vibrio cholerae
serotype O1
Haemophilus
influenzae KW20
Pseudomonas
aeruginosa PAO1
Xylella fastidiosa
9a5c
Type II
IB
IC
BaeS PhoR
BasS RstB
CpxA YbcZ
CreC YehU
EnvZ YfhK
KdpD YgiY
VC0303
VC0720
VC1319
VC2693
VC2713
VCA0531
VCA1104
ArcB
BarA
EvgS
RcsC
TorS
AtoS
HydH
NtrB
VC0622
VC1349
VC1445
VC1653
VC1831
VC2369
VC2453
VCA0709
VCA0736
HI1378
HI1707
PA0464
PA2810
PA0757
PA3191
PA0930
PA3206
PA1158
PA3271
PA1396
PA4036
PA1438
PA4102
PA1636
PA4380
PA1798
PA4777
PA1976
PA4886
PA1992
PA5199
PA2480
PA5361
PA2524
PA5484
PA2687
XF0323
XF0973
XF2535
XF2592
HI0220
VC1084
VC1639
VC1085
VC1156
VC1315
VC1521
VC1925
VC2136
VC2748
VCA0141
VCA0211
VCA0705†
VCA0719
–
–
PA0928
PA1611
PA2583
PA2824
PA3044
PA3462
PA3946
PA3974
Type III
Type IV
CheA
Unclassified
PhoQ*
PhoQ
PA1098
PA4293
PA1243
PA4398
PA1336
PA4494
PA2177
PA4546
PA2571
PA4725
PA2882
PA5124
PA4117
PA5165
PA4197
PA5512
PA1180
XF1455
XF1849
XF2546
XF0390
DcuS
DpiB
VC0791
VC1088
VC1605
NarQ
NarX
UhpB
B2380
YehU
CheA
VC1276
VCA0675
VCA0683
VC0694† VC1397
VCA0851† VC2063
VCA1095
–
VCA0257
VCA0565
VCA0238
VCA0522
–
HI0267
–
PA0600
PA2656
–
PA5262
–
PA0178
PA1979
PA0413
PA3878
PA1458
–
PA3078
PA3704
PA4112
PA4856
PA4982
XF0853
–
–
XF1625
XF1952
XF2577
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D. -j. K I M a n d S. F O R S T
Table 5 (cont.)
Genome
Neisseria meningitidis
MC58
Neisseria meningitidis
serogroup A Z2491
Rickettsia prowazekii
Madrid E
Helicobacter pylori
26695
Campylobacter jejuni
NCTC 11168
Type I
Type III
Type IV
CheA
Unclassified
IA
IB
NMB0594
NMB1792
NMA0670
NMA0797
RP426
–
NMB0114†
–
–
NMB1249
–
–
NMB1606
–
NMA0160
–
–
NMA1418†
–
–
NMA1803
PhoQ*
–
RP614
–
–
–
–
–
RP229
RP465
–
HP0244
–
–
–
–
–
–
Cj0793
–
–
–
–
–
AtoS
–
–
–
–
–
CP0164
–
–
–
–
–
–
–
NtrB
–
–
–
–
–
–
–
TC0752
–
–
–
–
–
–
BB0420 BB0764
–
–
–
–
–
–
–
–
–
BB0567
BB0669
TP0363
–
–
–
Rv0845
–
–
–
Chlamydophila
–
pneumoniae CWL029
Chlamydophila
–
pneumoniae AR39
Chlamydia
–
trachomatis serovar
D
Chlamydia
–
trachomatis MoPn
Borrelia burgdorferi
–
B31
Treponema pallidum
–
Nichols
Mycobacterium
Rv0490
tuberculosis H37Rv Rv1028c
Rv0758
Rv1032c
Rv0982
Rv3245c
Rv0601c
Rv3764c
Rv0902c
Bacillus subtilis 168 PhoR
ResE
Synechocystis sp.
PCC 6803
IC
Type II
–
TP0520
–
–
HP0392 HP0164
HP1364
Cj0284c Cj1262
Cj1226c
Cj0889c
Cj1222c
Cj1492c
–
–
Rv2027c
Rv3132c
Rv3220c‡
–
KinA
KinB
–
CitS
YdbF
ComP YocF LytS
DegS YvfT YesM
YclK
KinC
YufL
YdfH YvqE YwpD
YkoH
YvrG
YkrQ
YkvD
YcbA
YfiJ YxjM
YhcY
YycG
sll0337
–
sll0474
slr0210
–
–
–
slr0311
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CheA
YtsB YbdK
YvcQ
YrkQ
YxdK
YccG
SpaK†
YvqB
–
sll0043
sll1229
Histidine kinase family
Table 5 (cont.)
Genome
Type I
IA
IB
sll0790
sll0798
slr0533
slr0640
slr1147
sll0698
sll0750
slr1400
slr0473†
slr2099
DR0744
DR2419
DR1174
DRA0050
DR1175
DRA0205
DR1606
DRB0090
DR2244
DRB0029
DR2328
DRB0082
DR2416
Thermotoga maritima TM0400
MSB8
TM0853
TM1258
TM1654
Aquifex aeolicus
–
VF5
Deinococcus
radiodurans R1
Methanobacterium
thermoautotrophicum delta H
–
Type II
IC
Type IV
CheA
Unclassified
PhoQ*
sll1228
slr0484
sll1353
slr1393
sll1672
slr1759
sll1871
slr1969
sll1888
slr2098
sll1905
slr2104
sll1003
sll1124
sll1475
slr0222
slr1324
DR0860
Type III
slr1212†‡
sll1296
sll1590
slr1805
sll1555
–
–
–
DRB0028
DR0577
–
–
DR0892
DR1227
DR1556
DRA0009†
–
–
mth444
TM1359
–
–
–
–
TM0702
–
–
–
–
–
–
–
–
–
Type III B‡
–
–
TM0127
TM0187
hksP1
hksP2
hksP4
–
mth123
mth560
mth174
mth619
mth292
mth823
mth356
mth901
mth446
mth902
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D. -j. K I M a n d S. F O R S T
Table 5 (cont.)
Genome
Type I
IA
Archaeoglobus
fulgidus DSM4304
Pyrococcus horikoshii
OT3
–
–
IB
AF1483
–
Type II
IC
–
–
Type III
Type IV
CheA
Unclassified
–
mth459
mth985
mth468
mth1124
Type II B§
–
–
AF1040
–
–
AF0021
AF1452
AF0208
AF1467
AF0450
AF1515
AF0770
AF1639
AF0893
AF1721
AF1184
AF2109
784830†
–
–
CheA
–
PhoQ*
–
* PhoQ-type HKs were found only in the γ-subclass of the Proteobacteria.
† HK not listed in the TIGR gene table.
‡ Subtypes (III B) that exist within Type III HK family.
§ Subtypes (II B) that exist within Type II HK family.
III and IV HKs possessed unorthodox kinase domains.
The predicted secondary structure of the different Hbox and X regions and the H to N distances in the
different HKs were characteristic for the various HK
types. The fifth HK type was composed of CheA
molecules in which the H-box (P1) domain is located at
the N terminus of the protein. Based of these findings,
several conclusions can be made concerning the HK
family of bacteria and archaea. (i) All bacteria sequenced
to date, with the exception of mycoplasmas, contain
HKs. The HK content was found to increase as the
size of the genome increased. In free-living bacteria
possessing larger genomes the HK content was relatively
high while in pathogenic bacteria possessing smaller
genomes, the HK content was relatively low. On the
other hand, the HK content in archaea was highly
variable with some archaeal genomes completely lacking
HKs. (ii) Type I HKs were predominant in bacteria with
the content of the different Type I subtypes varying
greatly. For example, V. cholerae contained 12 Type IC
HKs while Synechocystis lacked these HKs. Similarly,
Synechocystis sp. contained 19 Type IB HKs while none
was present in B. subtilis. In contrast, Type I HKs were
not prevalent in archaea. (iii) Unlike bacterial HKs,
archaeal HKs were generally not organized in operons
with RRs. Some archaeal genomes possessed signifi-
cantly more HKs than RRs. (iv) The Gram-positive
bacteria analysed in this study contained a relatively
high content of Type III HKs. Similarly, Grebe & Stock
(1999) found that four of the eight HKs of the Grampositive bacterium Streptomyces coelicolor belonged to
the Type III (HPK7) group. (v) Hybrid HKs were found
in bacteria but have not yet been identified in archaea.
Interestingly, all known eukaryotic HKs belong to the
hybrid (Type IB) HK group (Grebe & Stock, 1999). (vi)
Finally, the HKs of Aqu. aeolicus and many of the HKs
in Helicobacter, Campylobacter and Halobacterium
remain unclassified. As more bacterial genomes are
sequenced, new HK types may be established that will
encompass these as yet unclassified HKs.
In this study, a genomics approach was taken to analyse
the HKs of bacterial and archaeal genomes. A different
approach was taken by Grebe & Stock (1999) in which
cluster analysis of 348 HKs led to a classification scheme
consisting of 11 HPK (histidine protein kinase) types.
A primary difference in the respective classification
schemes is found in the Type I group which was
separated into four different HPK types (HPK 1–4) in the
Grebe & Stock (1999) study. For example, the NtrBrelated HKs were placed in the HPK 4 group while
phylogenetic analysis (Fig. 2) placed these HKs within
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Histidine kinase family
the Type I (Type IC) group. In addition, Type II HKs
were separated into a bacterial group (HPK 5) and an
Arc. fulgidus group (HPK 6) by Grebe & Stock (1999).
Similarly, the Type III HKs were separated into a
bacterial group (HPK 7) and an Mbc. thermoautotrophicum group (HPK 11). HKs that did not cluster
within a defined HK group remained unclassified in our
study while Grebe & Stock (1999) either did not include
these HKs or gathered them into a separate subgroup.
Thus, we identified 36 HKs in B. subtilis with YvcQ,
YxdK and YtsB remaining unclassified (Table 5), while
Grebe & Stock (1999) identified 31 HKs and placed
YvcQ, YxdK and YtsB in their own subgroup (HPK3i).
We show that bacteria possessing larger genomes
contained several different HK types while archaeal
genomes either lacked HKs or possessed a HK family
consisting of a specific type. Arc. fulgidus and Mbc.
thermoautotrophicum possessed one Type I HK and a
large family of either Type II or III HKs, respectively.
These findings raise the question of why Type II and III
HKs, rather than Type I HKs, have expanded in different
archaea. Furthermore, it appears that the different HK
types arose in bacteria and were acquired by archaea via
lateral gene transfer (Grebe & Stock, 1999). Presumably,
Arc. fulgidus acquired a Type II HK gene from one
bacterial source while Mbc. thermoautotrophicum
acquired a Type III HK from a different bacterium. It is
of interest to consider whether different HK types
possess distinct functions that allow micro-organisms to
exploit specific ecological niches. Biochemical studies
have almost exclusively focused on the Type I HKs. A
comparison of the biochemical and structural properties
of the various HK types may reveal differences that
could further our understanding of the role that HKs
play in allowing micro-organisms to adapt to specific
environmental conditions.
ACKNOWLEDGEMENTS
We are grateful to A. Wolfe and B. Weisblum for their helpful
discussions and critical reading of this work. We thank D.
Saffarini, C. Wimpee and B. Boylan for their suggestions and
discussions during the course of this study.
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.................................................................................................................................................
Received 13 March 2000 ; revised 8 January 2001 ; accepted 25 January
2001.
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