Microbiology Department, Pacific Northwest National Laboratory, 902 Battelle Blvd, PO Box 999, Mail Stop P7-50, Richland, WA 99352, USA
Correspondence
Weiwen Zhang
Weiwen.Zhang{at}pnl.gov
Liang Shi
Liang.Shi{at}pnl.gov
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ABSTRACT |
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INTRODUCTION |
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In addition to the prototypical TCSTSs described above, a more complex version of this phosphotransfer scheme was also discovered in both prokaryotic and eukaryotic cells (Appleby et al., 1996). This system involves multiple phosphotransfer steps with often more than two proteins. Three types of multiple-step phosphorelay systems have been revealed. The first pathway is exemplified by the system that governs the initiation of sporulation in Bacillus subtilis. This phosphorelay cascade begins with the autophosphorylation of one of the three sensor kinases, KinA, KinB or KinC. The phosphoryl group is then transferred to a receiver domain in the regulator Spo0F. The Spo0F then serves as a phosphodonor for Spo0B, which is phosphorylated on a His residue. Finally, the phosphoryl group completes its course by transfer to an Asp in Spo0A (Burbulys et al., 1991
). The second and third type of multiple-step phosphorelay involve a hybrid-type HK in which both the HK domain and the RR receiver domain are present within a single protein. The second type has an intermediate His-containing phosphotransfer (HPT) domain in the same molecule, whereas in the third type, the HPT domain is contained on a separate protein. In the hybrid-type HK systems the phosphoryl group is first transferred from a His to an Asp residue within the hybrid HKs, then through the HPT domain or protein and is subsequently transferred to a cytoplasmic RR (Fig. 1
). It has also been suggested that protein phosphatases, such as the sixA gene in Escherichia coli, may be implicated in the HisAsp phosphorelay through regulating the phosphorylation state of the HPT domain (Ogino et al., 1998
). There are three well-studied cases where these hybrid HK mechanisms are utilized. The first is the BvgSBvgA system controlling the transcriptional regulation of virulence factors in Bordetella pertussis, in which the BvgS protein contains the HK domain, the receiver domain and the HPT domain (Uhl & Miller, 1996
) (Fig. 1a
). The second is the Sln1pYpd1pSsk1p system governing osmoregulation in the yeast Saccharomyces cerevisiae. In this system the HPT domain is contained on Ypd1p, a separate protein of 167 residues (Posas et al., 1996
) (Fig. 1b
). The third is the RcsCYojNRcsB signalling pathway, implicated in capsular synthesis and swarming behaviour in E. coli (Takeda et al., 2001
; Clarke et al., 2002
). In this system, the HPT domain is present at the C terminus of the protein YojN, which shows a similarity to RcsC, particularly in the HK domain, although the crucial autophosphorylation His site is missing (Takeda et al., 2001
; Clarke et al., 2002
) (Fig. 1c
). Early results from the analysis of HK domain architecture from a limited number of prokaryotic and eukaryotic genomes showed that most eukaryotic HKs are of the hybrid type, while only a small proportion of prokaryotic HKs contain both the kinase and receiver domains in a single HK molecule. It has thus been suggested that TCSTSs in prokaryotes generally use a simple two-component phosphotransfer scheme, whereas phosphorelays and hybrid HKs dominate two-component signalling in eukaryotes (West & Stock, 2001
; Oka et al., 2002
; Catlett et al., 2003
). However, in recent years more hybrid-type HKs have been identified from various bacterial genomes (Xu et al., 2003
; Rabus et al., 2004
; W. Zhang and others, unpublished data), suggesting that the role of multiple-step phosphorelay systems in prokaryotes might have been underestimated.
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METHODS |
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Identification of HPT.
All known HPT proteins from microbial sources, along with HPT domains from proteins identified as hybrid-type HKs by SMART in this study, were used as query sequences in two separate searches for HPT gene homologues. The first search was performed against the 156 complete microbial genomes contained in the OMINOME Pep database of TIGR using BLASTP (http://tigrblast.tigr.org/cmr-blast/) and the second was against the NCBI sequence database using BLASTP (http://www.ncbi.nih.gov/blast). Both searches used an E value threshold of <0·01.
Sequence alignment and phylogenetic analysis.
Sequence alignments were performed using the default parameters of the CLUSTALW program originally developed by Higgins & Sharp (1988), available from the LaserGene software package (DNAStar) and PAUP* 4.0 beta version (Blumenberg, 1988
) with an alignment gap penalty of 10·00 and a gap length penalty of 0·1. Confidence levels were determined by analysing 100 bootstrap replicates. For phylogenetic classification of kinase and receiver domains, functional domains of all known HKs and RRs in E. coli and Bac. subtilis were extracted and used as indicators for each phylogenetic group according to the method described previously (Koretke et al., 2000
).
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RESULTS |
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Phylogenetic analysis of kinase and receiver domains of hybrid-type HKs
The finding that hybrid-type HKs were unevenly distributed across microbial species leads to several immediate questions. First, did all hybrid-type HKs share the same ancestor or were they formed as the result of lateral events independently occurring in each species under specific selective pressure? Second, in 26 bacterial genomes with large numbers of hybrid-type HKs, what evolutionary mechanism was involved in their expansion? Is the same mechanism shared by all species? To address these questions, independent phylogenetic analyses were performed using sequences of functional kinase domains from HKs, and using the functional receiver domains from RRs, respectively. To help define the phylogenetic subfamilies to which these domains belong, the functional domains of all known TCSTSs from E. coli and Bac. subtilis were also extracted and included in the phylogenetic analysis. Phylogenetic trees of kinase and receiver domains were generated for each species from the aligned sequences and the confidence of the tree topology was evaluated.
In an earlier study (Koretke et al., 2000), the phylogeny constructed from a limited number of genomes showed that hybrid-type HKs were clustered together in one clade. In addition, they all shared the same root in the phylogenetic tree, implying that the hybrid-type HKs may have been generated before the divergence of microbial species, and that the kinase and receiver domains then evolved as a single unit into the present-day hybrid-type HKs. The group was thus conveniently named as Hybrid phylogenetic group (Pao & Saier, 1997
; Koretke et al., 2000
).
In this study, we included all the kinase and receiver domains from the hybrid-type HKs we identified, and were therefore able to perform phylogenetic analyses in more detail. The domains were assigned to several known phylogenetic subfamilies (Cit, Nar, Ntr, Pho and Hybrid groups) according to their clustering characteristics. For those domains not showing a clear clustering pattern with any of the above subfamilies, they were classified as the Other category. The results showed that although most of the kinase and receiver domains belonged to the Hybrid phylogenetic subfamily, some of them were clustered into the Ntr phylogenetic subfamily (containing systems regulating nitrogen assimilation, acetoacetate metabolism and hydrogenase activity in E. coli) (Stoker et al., 1989), and the Pho phylogenetic subfamily (containing systems involved in phosphate regulation, virulence, osmoregulation and anaerobic nitrite reduction in E. coli) (Stock et al., 1989
), suggesting that the members of hybrid-type HKs could be phylogenetically different.
Further analysis showed that the kinase and receiver domains from the same hybrid-type HKs were not necessarily located in the corresponding phylogenetic subfamily. For example, in Nostoc sp. PCC 7120, 49 kinase domains were clustered into Cit (1, number of kinase domains), Ntr (11), Pho (4), Hybrid (29) and Other (4) subfamilies, while its 59 receiver domains were clustered into Ntr (21), Pho (1), Hybrid (32) and Other (5) subfamilies, respectively (Table 2). In Bact. thetaiotaomicron all 41 kinase domains were clustered into the Hybrid clade, but only 8 of the receiver domains located to their cognate phylogenetic clade, while the other 33 actually belonged to the Pho phylogenetic subfamily (Table 2
). Examination of our data suggests that species from the same genus may have similar, but not identical, patterns of their HK and receiver domains in term of the subfamilies to which they belong. This is exemplified in the cases of Xan. axonopodis and Xan. campestris, or of Ps. aeruginosa, Ps. putida and Ps. syringae. Differences become even more obvious when comparing species across higher classification groups to determine to which subfamilies their domains belong. For example, two cyanobacteria have very different phylogenetic origination patterns for their kinase and receiver domains: in Nostoc sp. PCC 7120 the HK and receiver domains are mainly from the Hybrid and Ntr phylogenetic groups, while those in Synechocystis sp. PCC 6803 are mainly from the Hybrid and Pho phylogenetic groups (Table 2
). These results suggest that hybrid-type HKs might not have originated from a common ancestor and that domain recruitment events occurred as lateral events during evolution. In addition, we found that some of the hybrid-type HKs contain more than one receiver domain (Table 2
).
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Sequence alignments of HPT domains from hybrid-type HKs or from separate HPT proteins were performed using the CLUSTALW program (Higgins & Sharp, 1988). The result showed that overall sequence similarity between various HPTs was low. The relatively conserved region was a region of approximately 30 aa in length starting from the forty-first amino acid in the N termini (the number shown in the case of TLR0349 from The. elongatus) (Fig. 3
), consistent with an early study with a limited number of HPT sequences (Rodrigue et al., 2000
). Histidine H44 is the only residue conserved through all HPTs, although several other residues, lysine K47, glycine G48, glycine G54 and glutamic acid E66 were also conserved in most HPTs (the number shown in the case of TLR0349) (Fig. 3
). Phylogenetic analyses were conducted with the HPTs identified (Fig. 4
). Although the HPT domains/proteins showed less than 20 % sequence identity, several recognizable clusters can be identified. However, no obvious correlation between the distribution of HPTs in each cluster and their taxonomic relationship was found, suggesting that the sequence diversification resulted mainly from specialization of function rather than bacterial speciation. All HPTs shared a single root in the phylogenetic tree, suggesting that there is a common ancestor for HPTs. This result is consistent with a previous observation that all HPTs share a common structural motif and active site (Kato et al., 1997
; Xu & West, 1999
).
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Phylogenetic analysis of additional sensory domains in hybrid-type HKs
The analysis showed that a fraction of prokaryotic hybrid-type HKs contained sensory domains (Table 1). Three types of sensory domains were most frequently found in these hybrid-type HKs: PAS domains that bind flat heterocyclic molecules such as haem and flavin and are involved in sensing energy-related environmental factors such as oxygen, redox potential or light (Taylor & Zhulin, 1999
; Taylor et al., 1999
); GAF domains involved in binding cyclic nucleotides (Aravind & Ponting 1997
); and the HAMP domain that is often found in various HKs, adenylyl cyclases, methyl-binding proteins and phosphatases (Galperin et al., 2001
). A total of 245 PAS domain sequences (mean of 65100 aa in length) were identified from hybrid-type HKs in prokaryotes using the SMART program. These sequences were then used in the construction of a phylogenetic tree. To help in the classification and definition of each phylogenetic cluster, a few dozen PAS domains with known function, obtained from other bacterial sources, were also used in the phylogenetic tree construction as described previously (Taylor & Zhulin, 1999
; Zhang & Shi, 2004
). It is obvious from the phylogenetic analysis that, although individual exceptions are present and overall bootstrap support was not high, PAS domains extracted from hybrid-type HKs tend to be clustered based on their putative physiological function rather than taxonomic relationship (data not shown). This finding suggested that PAS domains with different functional specialties were recruited into hybrid-type HKs as lateral events.
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DISCUSSION |
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Hybrid-type HKs were found selectively enriched in very diverse bacterial species, from photosynthetic cyanobacteria to various pathogenic bacteria (Table 1), indicating that multiple-step phosphorelay may have special signalling properties such that the evolution and expansion of this unique family of signalling molecules occurred in response to unique challenges that these bacteria faced. Compared with simple scheme of TCSTSs, multiple-step phosphorelay has been suggested to have three major advantages: (i) presence of kinase and receiver domains in one protein may constrain signal amplification, modularity or cross-talk between components of TCSTSs (Bijlsma & Groisman, 2003
); (ii) because of the involvement of HPT, the mechanism provides greater versatility in signalling strategies and a greater number of potential sites for regulation (Grossman, 1995
; Appleby et al., 1996
); and (iii) the multiple phosphorylation sites of the phosphorelay could provide more junction points for communicating with other signalling pathways (Appleby et al., 1996
).
Unlike HKs in other phylogenetic subfamilies, such as Pho and Ntr (Koretke et al., 2000), several observations emerging from this study suggest that there was no single ancestor for hybrid-type HKs. First, the survey of hybrid-type HKs across prokaryotic genomes showed that their distribution did not follow any taxonomic relationship; species with very close relationship could be quite different in terms of the total numbers and percentage of hybrid-type HKs. For example, Synechocystis sp. PCC 6803 contains 11 hybrid-type HKs, while Synechococcus sp. WH8102 has none. Second, independent phylogenetic analysis of kinase and receiver domains from hybrid-type HKs showed that hybrid-type HK may have kinase and receiver domains with different phylogenetic origins. Further support was also provided by the observation that hybrid-type HKs from the same species often have multiple combinations of individual kinase and receiver domains (based on their phylogenetic origins), indicating that lateral recruitment events were involved in the evolution of these proteins. The results demonstrated that domain recruitment followed by gene duplication may be responsible for the expanding of hybrid-type HKs in bacteria.
No correlation was found between the number of hybrid-type HKs and HPTs in prokaryotic genomes, which was consistent with a previous study in fungal genomes (Catlett et al., 2003). Even more interesting, 41 % of the prokaryotic genomes with hybrid-type HKs do not have any identifiable HPT sequences. This observation raises questions regarding the mechanism by which prokaryotic multiple-step phosphorelay systems function and how the specificity of signal transduction is being controlled. One plausible explanation might be that the prokaryotic systems are indeed functioning like the eukaryotic systems, but that most of the bacterial HPT proteins were not identified in this study because of low sequence similarity to known HPT proteins (Rodrigue et al., 2000
). Another hypothesis is suggested by a mechanism that has been proposed for Arabidopsis HPTs involving chaperone-like proteins that associate with TCSTSs at the membrane/cytoplasm interface and/or guide the phosphorylated HPT into the nucleus or other subcellular compartments (Pawson & Scott 1997
; Grefen & Harter, 2004
). However, it is unclear whether there is any similar mechanism involved in guiding the specialization of phosphorylation in prokaryotes. Finally, although almost all known hybrid-type HKs appear to function in multiple-step phosphorelays, in which the phosphate is transferred from the receiver domain of the hybrid HK to a second His residue in an HPT domain and then to RR (Chang & Stewart, 1998
; West & Stock, 2001
; Catlett et al., 2003
), it is still possible that phosphorelay may not be the only use of this architectural design and it is therefore possible that not all of the prokaryotic hybrid-type HKs are involved in multiple-step phosphorelay. An example of this is seen in Agr. tumefaciens, where the attached receiver domain of VirA, a transmembrane hybrid HK, functions as an autoinhibitory domain. In its unphosphorylated state, this receiver domain interacts with the transmitter module and prevents the transmitter from autophosphorylating and serving as a phosphodonor to its cognate response regulator VirG (Chang et al., 1996
; Appleby et al., 1996
).
In conclusion, this study presents a survey of the distribution and evolutionary analysis of the components involved in multiple-step phosphorelay in prokaryotes, and constitutes a basis for further exploration of their physiological functions.
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ACKNOWLEDGEMENTS |
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Received 22 February 2005;
revised 5 April 2005;
accepted 18 April 2005.
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