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Structural Classification of Bacterial Response Regulators: Diversity of Output Domains and Domain Combinations

Michael Y. Galperin J. Bacteriol. 2006, 188(12):4169. DOI: 10.1128/JB.01887-05.

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nih. TPR. 150). 188.01887-05 Vol. CheC. RpoE. e. June 2006. encoded in complete genomes of 200 bacterial and archaeal species. enzyme activity. CAP_ED.” Spo0A-type. and MerR) account for an additional 6%. with the methylesterase (CheB) and chemotaxis modulator (CheW) domains. National Library of Medicine. 75). which controls flagellum ejection and stalk formation during the C. 4. In this work.nih.ncbi. Phone: (301) 435-5910. the N-terminal REC domain packs against the active site of the C-terminal methylesterase domain and inhibits methylesterase activity by restricting access to the active site (34). a secondary messenger in bacteria (99. as well as in some other regulatory pathways (10. In PleD. protein. Structural characterization of the DNA-binding domains of various response regulators revealed several variations on the common helix-turn-helix (HTH) theme. were identified and classified by their domain architectures. which increase the propensity of the REC domain to form dimers. MD 20894.org/ on May 19. the presence of the N-terminal CheWlike domain was shown to stabilize the phosphorylated state of the C-terminal REC domain (40.asm. Bethesda. National Institutes of Health.org/. In the CheB-type response regulator. and/or protein-protein interactions in response to environmental challenges. 126. CheB. In Vibrio cholerae response regulator VieA. 87. In addition to forming associations with various DNA-binding domains. 112. both of which participate in the adaptation to attractants during chemotaxis (61). which has diguanylate cyclase activity that produces bis-(3 35 )-cyclic diguanosine monophosphate (c-di-GMP). Maryland 20894 Received 12 December 2005/Accepted 28 March 2006 CheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. 124. 130). 127. 2012 by guest * Mailing address: National Center for Biotechnology Information. 150).gov. 89) and the CheY-like receiver (phosphoacceptor) domain was identified as their common regulatory module (95. assigned to known domain families.g. evolutionarily stable. 61). the REC domain) from Escherichia coli and other organisms confirmed that it is an autonomously folding.1128/JB. National Library of Medicine.00 0 doi:10. crescentus life cycle (1. some of which have been experimentally verified (94. In the Bacillus subtilis CheV protein.JOURNAL OF BACTERIOLOGY. Structural characterization of the CheY-like receiver domain (hereafter. 4169–4182 0021-9193/06/$08. 100). PP2C. and HPt) domains. 39. the REC domain can function as a stand-alone module. The typical scheme of bacterial two-component signal transduction involves signal sensing (ligand binding or other conformational change) by a sensory histidine kinase that leads to its autophosphorylation. Previously uncharacterized output domains were analyzed and.nlm. p. The REC domain can also form combinations with other signaling domains. HD-GYP. Bethesda. 138. which controls biofilm for4169 Downloaded from http://jb. NarL. 88. These conformational changes.gov/Complete_Genomes/RRcensus. followed by phosphoryl transfer to the Asp residue in the N-terminal REC domain of the cognate response regulator. or newly described domains of unknown function. It has been 20 years since the first bacterial response regulator genes were sequenced (35. Fax: (301) 435-7793.610 response regulators. The diversity of domain architectures and the abundance of alternative domain combinations suggest that fusions between the REC domain and various output domains is a widespread evolutionary mechanism that allows bacterial cells to regulate transcription.asm. EAL. 78. are used by bacterial and archaeal cells to transmit and propagate a wide variety of environmental and intracellular signals (29. Its propensity to protein-protein interactions plays a key role in the chemotaxis machinery. 57. Sequence comparisons revealed additional types of DNA-binding domains in certain response regulators.nlm.g. . transcriptional regulators with other DNA-binding domains (LytTR. GAF. 147) whose conformation undergoes a distinctive change upon phosphorylation (65. It also forms other types of response regulators by associating with certain enzymatic or protein-binding domains. 79. in some cases. and 150 for reviews and reference 43 for a historical perspective). RNA-binding (ANTAR and CsrA). and Fis-like structures (12. Transcriptional regulators of the OmpR. e. 2. OmpR-type “winged helix. see references 58 and 109 for reviews). 52).or ligand-binding (PAS. which affects the properties of the C-terminal DNA-binding domain (127.. and HisK). The conformational change occurring upon phosphorylation of the REC domain apparently disrupts this interaction and relieves the methylesterase domain from inhibition by REC (34). exemplified by the NarL-type. in the Caulobacter crescentus PleD response regulator. 12 Structural Classification of Bacterial Response Regulators: Diversity of Output Domains and Domain Combinations† Michael Y. YcbB. The remaining one-third is represented by the stand-alone REC domain ( 14%) and its combinations with a variety of enzymatic (GGDEF. 113). AraC. The complete list of response regulators encoded in each of the 200 analyzed genomes is available online at http://www. the N-terminal REC domain is fused to an inactivated REC domain and a C-terminal GGDEF domain.. 127. National Institutes of Health. E-mail: galperin @ncbi. † Supplemental material for this article may be found at http://jb . compact structural unit (125. Fis. Spo0A. see references 55.html. No. Galperin* National Center for Biotechnology Information. and NtrC families were found to comprise almost 60% of all response regulators.

The PSIBLAST searches used strict inclusion threshold E values of 10 4 to 10 5. bsl2179. three species of Brucella) had merged RefSeq entries. the REC domain is associated with the EAL domain.4170 GALPERIN J. matched against UniProt (13). 85. 73. The complete list of REC-containing proteins encoded in each of the 200 analyzed genomes was compiled separately for each bacterial phylum based on the results of iterative PSI-BLAST searches (3) of the NCBI’s Reference Sequence (RefSeq) database (103). Whenever possible. and Mesorhizobium loti msl3517 and mlr3700) (see the file RRseqUpdate in the supplemental material). Classification of REC-containing proteins. The genome sequences were downloaded from the NCBI’s Genomes database or searched directly on the NCBI website (http://www. 76. and discrepancies were resolved on a case-by-case basis. were analyzed separately and.nlm. The sequences were also Downloaded from http://jb. and several other bacteria have been tabulated and classified (48. There have been several attempts to compile comprehensive lists of response regulators in all sequenced microbial genomes (11. B. The great majority of all response regulators encoded in complete prokaryotic genomes combines the REC domain with a DNA binding HTH domain. according to the NCBI Genomes database listing. and COG (60. In this work. Firmicutes[orgn]). using the UniProt batch retrieval tool. 109). These domains are well studied and have known three-dimensional structures (12. We have already discussed the most common errors in annotating signaling proteins and suggested that. Corrected open reading frames for nine genes. protein-binding. sequences of incomplete genomes were excluded using the srcdb_refseq_provisional[prop] modifier. 134).gov/BLAST/) using the PSI-BLAST (3) tool. Response regulators of the latter type are referred to here as the NtrC family. and Pfam domain databases (14. 114.. sequence database searches for relatives of certain response regulators often retrieve nonhomologous protein sequences that share only the REC domain (43). However. The results of this analysis are shown in Tables 1 and 2. In most instances. In the absence of experimentally characterized representatives. The query sequence and the position-specific scoring matrix are both available in the supplemental material.. rather than on sequence similarity of any given domain (38. 85) using the CD search tool (86) with relaxed cutoff values. sequenced by 20 September 2005.g. The response regulator sets encoded in E. Bacteroides thetaiotaomicron BT3258. and grouped according to their domain composition. Typhi. Synechococystis sp. identified as members of existing or novel domain families. 121). Response regulators with DNA-binding output domains. Unfortunately. 1). and Typhimurium. were included in the list. Streptococcus pneumoniae. controls biosynthesis of extracellular polysaccharide in Xanthomonas campestris (45. as well as to list response regulators in microbial genome databases. 111. Bradyrhizobium japonicum bsl1713. and ligand-binding domains. adjusting as necessary. the protein counts were compared to the published data. BACTERIOL. enzymatic. The former type of domain architecture was first described in the RegA and PrrA response regulators from Rhodobacter sphaeroides (36. using the CDD Domain viewer (86). REC-AraC and RpoE-REC). Paratyphi. 51. Hence.g. UniProt entry Q9WYT9) and a precomputed position-specific scoring matrix. 91.0) parameters. I present here a comprehensive domain-based classification of the response regulators encoded in completely sequenced genomes of 200 bacterial and archaeal species and describe domain architectures that involve the REC domain and known DNA-binding. typically the first publicly released one. the extreme diversity of REC domain combinations encoded in recently sequenced microbial genomes continues to generate problems during genome annotation (43. discrepancies could be attributed to different treatments of highly diverged and truncated sequences.org/ on May 19. 66. 74. HTH domains of the response regulators have been grouped here by sequence similarity.nih. 101. such sequences were defined as ones showing up in the PSI-BLAST searches but not recognized as containing the REC domain by RPS-BLAST comparison against CDD. PSI-BLAST searches were also run against selected genomes using the NCBI’s Genomic BLAST tool (31). where available (e. coli. subtilis. owing to the relatively high sequence conservation of the REC domains. Only one representative genome per species was chosen. Potential false-positive hits were checked at every step of PSIBLAST using the CDD Domain viewer (86) and manually removed (unselected) from the hit list for each iteration of PSI-BLAST. as described earlier (42). as well as several new domains. Identification of REC-containing proteins. and bsr2863. Haloarcula marismortui rrnAC1630 and rrnAC3385. The lists of REC-containing proteins from each complete genome were checked against the CDD. AAD35552.ncbi. 115) and is referred to here as the PrrA family. typically either of NarL-type or of OmpR-type winged HTH family (Fig. 90. following the approach utilized previously in the COG database (135). To account for the cases where different species (e. 145).g. The phylogenetic representation and the total numbers of REC-containing proteins encoded in each given genome were estimated using the Taxonomy Report option in the BLAST output. Low-scoring hits (potential false negatives) were inspected on a case-by-case basis by comparing them against the CDD and Pfam domain databases (14. 141). 95. The analyzed set included complete genome sequences of 200 bacterial and archaeal species. 84. or enzymatic output domains have been put into separate categories (Table 1). and linked to the corresponding entries in the Pfam database (14). In each case. To assist in this process. mation by this organism (137). To achieve proper granularity. families of response regulators were named based on their domain architectures (e. These were typically excluded from the total count but still listed (marked with asterisks) in Table S1 in the supplemental material. not described previously.. 157). The domain architecture of the Mlr3700 protein is discussed in the Results. the search was initiated with the 122-amino-acid sequence of the Thermotoga maritima CheY protein TM0468 (GenBank accession no. 146. As an exception. unless exact function of the newly described protein is known.. 131). A factor of inversion stimulation (Fis)-type DNA binding domain (71. The families of response regulators were named after their experimentally characterized representatives. 70. followed by manual analysis of the outputs. 97. its annotation should be based on its domain composition. and were repeated until convergence. and three serovars of Salmonella enterica. have been submitted to the NCBI RefSeq database. COG. 2012 by guest RESULTS Response regulators encoded in prokaryotic genomes show a great variety of output domains and domain combinations.g. 73) is also commonly found in response regulators. if appropriate. A combination of the REC domain with another c-di-GMP-specific phosphodiesterase. MATERIALS AND METHODS Data sources. or Pfam databases with default or relaxed (E value of 1. such as KEGG. 30. The database search space was limited to the given phylum (e. the HD-GYP domain. two strains of E.asm. OmpR-like and Spo0A-like). as listed on the NCBI’s Entrez Genomes website (151). classification of response regulators has to be based primarily on their domain architectures and structures of the constituent domains. 134). coli. 1). a c-di-GMP-specific phosphodiesterase (22. not assigned to any known protein domain. 148).. Other widespread DNA-binding domains in re- . Any sequence fragments longer than 90 amino acid residues. All N-terminally truncated sequences were manually inspected to see if the apparent truncation could be due to the incorrect selection of the start codon during automated annotation. after its best-studied representative (65. either directly fused to the REC domain or containing an additional AAA -type ATPase domain (Fig. COG. 107). for which this proved to be the case (Bacillus cereus BC5352. SENTRA. K12 and O157:H7. Response regulators that contained RNA-binding.

3%) 1526 (33. d Includes 50 response regulators that contain both GGDEF and EAL domains. if any. 188. For example. 108). 111 116 19 110 Downloaded from http://jb. was shown to be related to the XRE-type HTH domain (PF01381).org/ on May 19. Of all the numerous RNA-binding domains described in the past several years (7). which has c-di-GMP-specific phosphodiesterase activity. The HD- . a variant of the widespread HD-type phosphohydrolase (PF01966). In some cases. A single instance of a response regulator formed by another RNA-binding domain.5%) 139 (3.4%)d 83 (1. 52) have a GGDEF-type output domain. 153). In transcriptional reg- ulators of the AmiR and NasT type. 2. this domain stimulates transcription by preventing transcription termination at rhoindependent terminators (96. Thus. In some instances. and a DNA-binding domain (131. Counting the response regulators containing any of these domains shows that each of them comprises more than 1% of the total set and can be found in various phylogenetic lineages (Fig. 95 94 73 106 119 34 28 46 45. 112).6%) REC wHTH HTH AAA-FIS LytTR FIS HTH_AraC ANTAR CheB GGDEF EAL HD-GYP PP2C (SpoIIE) HisKA-HATPase CheW PF00072 PF00486 PF00196 PF00158 PF02954 PF04397 PF02954 PF00165 PF03861 PF01339 PF00990 PF00563 PF07228 PF00512 PF02518 PF01584 125. S2 in the supplemental material).1%) 862 (18.VOL.asm. which combines an N-terminal REC domain with a C-terminal methylesterase domain. This work revealed a number of additional combinations of the REC domain with previously described DNA-binding domains. has been commonly found in response regulators (Table 1). 2006 DOMAIN ARCHITECTURES OF BACTERIAL RESPONSE REGULATORS TABLE 1. only one. if available. 2012 by guest The table lists response regulators with at least 40 representatives in the analyzed set. The latter domain retained catalytic activity in the absence of REC or when the REC domain was phosphorylated (81. Response regulators with RNA-binding output domains. (beta-proteobacterial transcriptional regulator. Widespread types of bacterial response regulators a Response regulator Typeb COG no. ANTAR (119). 120. in the set (% of total) Name Output domain Pfam entry 4171 Reference(s) Stand-alone REC DNA-binding OmpR-like NarL-like NtrC-like LytR-like PrrA-like REC-AraC (YesN-like) RNA-binding. 119). a previously uncharacterized N-terminal output domain in response regulators of the CV0537 family.8%)d 72 (1.” Most of these newly described domain combinations are relatively rare and have a narrow phylogenetic distribution (Table 2). which has diguanylate cyclase activity (28. whose similarity. whose structure is still unknown (Table 1). newly identified output domains could be linked to known HTH domains by PSI-BLAST or CD searches. Description of the domain structure.7%) 393 (8.0%) 48 (1.0%) 48 (1. including cases where the HTH domain occupies the N-terminal part of the protein (Table 2). was found in Rhodopirellula baltica protein RB8820 (Table 2). deposited in the Pfam database as domain PF08667). nine haloarchaeal response regulators annotated as Hlx1 through Hlx6 (Table 2) contain a new output domain (renamed here HalX) (see Fig. 137). Response regulators with enzymatic output domains. encoded in Chromobacterium violaceum and Burkholderia spp. whereas VieA-type response regulators combine the REC domain with the EAL domain. Size (aa) No. 116) and is often linked to the regulation of RNA polymerase sigma factors (143. found in Cro and cI repressors (see Fig.9%) 72 (1.6%) 46 (1. however. 1 and Table 1). a fusion of the REC domain with an N-terminal CsrA domain (50. Recognition of the REC domain as a universal regulatory domain was prompted by sequencing of the chemotaxis protein CheB.0%) 88 (1. S1 in the supplemental material). PleD-like response regulators (1. All such response regulators have been classified as “uncharacterized. found in at least two bacterial phyla.0%) 40 (0. This COG contains only the output domain of this response regulator. Two more common enzymatic output domains in response regulators are the protein phosphatase of PP2C type (RsbUlike) and the phosphodiesterase HD-GYP. Subsequent studies revealed response regulators that contain the REC domain in association with other enzymatic domains. to the homeodomain-containing animal Hlx proteins is totally spurious.3%) 154 (3. 124). The former domain dephosphorylates Ser P and Thr P residues in a variety of proteins (64.9%) 107 (2. 146 88 12 76. AmiR/NasR-like Enzymatic Methylesterase (CheB-like) Diguanylate cyclase (PleD-like) c-di-GMP phosphodiesterase (VieA-like) c-di-GMP phosphodiesterase (RpfG-like) Protein phosphatase (RsbU-like) Histidine kinase Protein-binding CheW-REC (CheV-like) a b c 0784 0745 2197 2204 3279 c 4567 4753 3707 2201 3706 2200 c 3437 2208 0642 0835c 120 240 240 450 250 170 260 180 300 310 370 360 350 350 300 659 (14. sponse regulators include the AraC-type HTH domain (106) and the LytTR domain (94). or sequence alignment. response regulators that were originally assumed to be DNAbinding showed no statistically significant similarity to any known DNA-binding domain. BetR.

HTH-REC RpoE-REC MerR-REC BetR-REC AlpA-REC HlxR–REC LysR-REC RNA-binding. which are then referred to as “hybrid” kinases. 2012 by guest 2172 1776 2114 0455 2345 2120 1215 2804 1639 0515 153 98. 83 This work This work 20 PF08663 GYP domain has been proposed to function as a c-di-GMP hydrolase. are far less common and found mostly in gamma-proteobacteria. The pglZ (phage growth limitation) gene of Streptomyces coelicolor A3 (2) is part of a four-gene operon that somehow controls phage propagation in this organism (128).org/ on May 19. Although this suggestion was consistent with participation of the HD-GYP-containing response regulator RpfG in regulation of extracellular polysaccharide production in Xanthomonas campestris (121) and with the wide distribution of the RpfG-type response regulators (Table 1). the REC domain is often found at the C terminus of sensory histidine kinases. phosphomutases.asm. 154 49 26 25 This work 139 155 93 50 15 14 5 2 15 6 5 2 1 1 1 14 13 6 5 3 1 1 2 1 4 1 PB005154 PF08664 PF00486 PF03704 PF00325 PF04542 PF04545 PF00376 PF08667 PF05930 PF01638 PF00126 PF02599 3947 0664 1595 2452 3311 1733 0583 Downloaded from http://jb. the c-di-GMP-specific phosphodiesterase activity of the HD-GYP domain in RpfG has been demonstrated in a direct biochemical assay (111). Reference(s) 78 113 152. PCC7120 Nostoc sp. PglZ is likely to have a similar enzymatic activity. PCC7120 Halobacterium sp. based on its peculiar phyletic pattern. Response regulators whose output domain is a protein phosphatase of CheC type. are often encoded on integrative plasmids (23). The PglZ domain. which include Salmonella enterica serovar Typhimurium protein STM4492. 129 156 77 72 132 133 102 This work This work 117 20 18 9 4 4 2 2 21 7 9 2 Desulfovibrio vulgaris Escherichia coli Xylella fastidiosa Haloarcula marismortui Geobacter sulfurreducens Geobacter sulfurreducens Bdellovibrio bacteriovorus Nostoc sp. BACTERIOL. Given that members of this superfamily typically function as phosphatases. found in response regulators from Porphyromonas gingivalis and Cyto- phaga hutchinsonii. The search . the PglZ protein and its close homologs have all the hallmarks of the alkaline phosphatase protein superfamily (see Fig. Recently.) BSU24220 (CAB14353) BSU02450 (CAB12039) DR2556 (AAF12095) glr1768 (BAC89709) CC3477 (AAK25439) TDE0855 (AAS11346) CV0537 (AAQ58214) DET1294 (AAW39407) rrnB0301 (AAV48466) SPO3037 (AAV96273) RB8820 (CAD75938) LA2951 (AAN50149) VCA0189 (AAF96102) Blr2288 (BAC47553) RSc0653 (CAD14183) Nfa52850 (BAD60137) Lxx09320 (AAT88820) MTH548 (AAB85054) Daro_0966 (AAZ45722) PG0928 (AAQ66063) VC1081 (AAF94240) RB10329 (CAD78826) PF04509 PF00211 PF00991 PF00070 PF02585 PF00535 PF00437 PF08665 PF08668 PF00069 Pfam entry Output domain COG no. 129). While its exact function is unknown. REC-HTH Spo0A-like YcbB (GlnL)-like REC-SARP (REC-HTH-BTAD) REC-CRP DNA-binding. 46).4172 GALPERIN TABLE 2. is another likely phosphatase. Family name. or phosphodiesterases (44). Response regulators with unusual domain organizations J. CsrA-REC Enzymatic Ser/Thr protein kinase RECRsbW or REC-RsbU-RsbW Phosphoaspartate phosphatase REC-CheC Adenylate cyclase REC-ACyc ParA family ATPase REC-Soj NAD(P)H:disulfide oxidoreductase REC-TrxB Poly-N-acetylglucos amine deacetylase REC-LmbE Glycosyltransferase REC–WcaA PilB-like ATPase REC-PulE Predicted phosphatase REC-PglZ Predicted phosphodiesterase REC-HDOD Ser/Thr protein kinase REC-STYK Protein-protein interaction REC-TPR (VieB-like) Hnr-like REC-HPt REC-PAS REC-GAF Ligand-binding REC-PilZ REC-cNMPbinding Uncharacterized PatA-type Ycf55-type REC-HalX OsaB-type Total no. In addition to response regulators. complementing that of the EAL domain (45. Example Organism name Bacillus subtilis Bacillus subtilis Deinococcus radiodurans Gloeobacter violaceus Caulobacter crescentus Treponema denticola Chromobacterium violaceum Dehalococcoides ethenogenes Haloarcula marismortui Silicibacter pomeroyi Rhodopirellula baltica Leptospira interrogans Vibrio cholerae Bradyrhizobium japonicum Ralstonia solanacearum Nocardia farcinica Leifsonia xyli Methanobacterium thermoautotrophicum Dechloromonas aromatica Porphyromonas gingivalis Vibrio cholerae Rhodopirellula baltica Gene name (accession no. which dephosphorylates the Asp P residue of REC (98. Hybrid histidine kinases and REC-HisK response regulators. domain organization DNA-binding. it has long remained unverified. NRC-1 Streptomyces coelicolor DVU2937 (AAS97409) RssB (AAC74317) XF2359 (AAF85158) RrnAC0674 (AAV45676) GSU1316 (AAR34692) GSU0877 (AAR34207) Bd3065 (CAE80821) all0521 (BAB72479) alr0960 (BAB72917) VNG2036G (AAG20197) SCO5749 (CAA19850) PF00515 PF01627 PF01627 PF01590 PF07238 PF00027 0457 2198 2202 2203 3215 0664 21 15 63 136 54 4 33 80. S3 in the supplemental material). Its homologs.

combining REC with the protein-binding CheW-like domain (Table 1). The sectors in the chart indicate the respective share of each domain combination and are colored similarly to the corresponding output domains. YwpD-like histidine kinases are members of complex signal transduction cascades operating inside the bacterial cell (41). The search for REC-containing proteins also revealed hy- brid histidine kinases which. PF07568. for example. Some of such fusion proteins contain periplasmic. HATPase_c or PF02518. and many other families are widespread in Bacteria. method used in this work retrieved hybrid histidine kinases as well as response regulators. cNMP-binding. TPR. In Bacteroides thetaiotaomicron. not ligand binding per se. The sector marked as REC-Fis REC-AraC represents all rare DNA-binding response regulators listed in Table 2. or HPt domains as the only output domains (Table 2). and there is no (other) sensory domain (Fig. or integral membrane sensory domains. BarA. signal transduction likely involves their interactions with other protein domains. output domains are devoid of (known) enzymatic activity and exert their effects through protein-protein interactions. only YwpD-like histidine kinases without any discernible signaling domains intervening between REC and HisK were counted as bona fide response regulators. Therefore. and TorS) out of 30 are hybrid. In any case. While response regulators of OmpR. sometimes in significant numbers. two separate subdomains of histidine kinases. and the catalytic one. so that they can only act as transcriptional regulators while their binding sites on the chromosomal DNA are positioned in the vicinity of the membrane. this domain organization is seen in 11 out of 17 hybrid histidine kinases. Some of them can be considered true synapomorphies—shared derived characteristics of the representatives of a particular group to the . Such proteins are encoded in a variety of bacterial genomes. Response regulators with protein-binding domains. coli. the YwpD protein differs from typical hybrid kinases in that its REC domain is located at the N terminus. VieA. extracellular. Domain architectures of the most common types of bacterial response regulators. 2006 DOMAIN ARCHITECTURES OF BACTERIAL RESPONSE REGULATORS 4173 Downloaded from http://jb. These “onecomponent” signal transduction systems (141). 36 out of 44 hybrid histidine kinases have tandem AraC-like DNA-binding domains at their C-termini (species-specific listings of hybrid histidine kinases are available in the files that are linked to Table S1 in the supplemental material). which could affect the enzymatic activity of the output domain (Fig. These include chemotaxis response regulators of the CheV type. in B. cereus protein BC3207. In Bacteroides fragilis strain YCH46. However. typically PAS and/or GAF. 188. For the purposes of this work. the separation between YwpD-like response regulators and hybrid histidine kinases is not clear-cut. GAF. While PAS and GAF domains are known to bind ligands. similarly to the response regulators of the PleD. YwpD-like histidine kinases can be considered yet another form of response regulators with enzymatic output domains whose activity is modulated by appropriate sensory histidine kinases.org/ on May 19. Genome analysis reveals numerous intermediate forms with additional signaling domains.VOL. and response regulators of the Hnr-type (see below). 1. exemplified by B. In E. 2). Clade-specific response regulators. subtilis. In some response regulators. EvgS. are treated here as a single HisK domain). look like fusions of classical histidine kinases with full-length response regulators. 2). This means that the only signal that could be sensed by the YwpD protein is the phosphorylation (or other modification) of its N-terminal REC domain. contain DNA-binding domains at their C-termini. 2012 by guest FIG.asm. HisKA. the dimerization/phosphoacceptor one. such as CAP_ED. NarL. and PF02518. Unfortunately. PF07730. represented by Pfam entries PF00512. Alternatively. RcsC. there are no hybrid kinases with the exception of the YwpD protein that combines a truncated REC domain with a HisK domain (for simplicity. The same could be true for other ligand binding domains. five histidine kinases (ArcB. the REC and HisK domains of such proteins might not be regulated at all and function solely as sinks for the phosphoryl residues. and RpfG families. in addition to the REC domains. some response regulators are found only in representatives of certain phylogenetic lineages. as well as response regulators that contain PAS. and PilZ domains (Table 2). these were subsequently separated based on their domain architectures.

Some of the domains are highly diverged and could be recognized only by searching the CDD database using relaxed stringency parameters.4174 GALPERIN J. gene names. Desulfovibrio vulgaris DVU2677 (18. Outside Firmicutes. Downloaded from http://jb. rrnAC1495 (12. exclusion of other groups—whereas others are encoded only in organisms with larger genomes and could have been lost in streamlined genomes of parasites and other small-genome organisms. the spo0A gene is inactivated by what authors claim is a verified frameshift (118). Spo0A. AAV45829). Haloarcula marismortui rrnAC0574 (4. AAV46539). and pNG7156 (13. Gloeobacter violaceus gll0634 (15. AAV48063). BACTERIOL. BAC46295). BAA10222). If so. Clostridiales. 2012 by guest FIG. BAB75796). which would make it a convenient laboratory strain but hardly a representative of the naturally occurring clostridia. Dechloromonas aromatica Daro_2847 (19. 2. Synechocystis sp. rrnAC2533 (6. Remarkably. Spo0A. rrnAC3361 (10. Domain architectures of response regulators with the histidine kinase (HisK) output domain. The master regulator of sporulation. Source organisms. rrnAC0848 (8. and 18 were considered bona fide response regulators. AAV48050). BAB73236). AAV45155). is shared by all spore-forming representatives of Firmicutes. Proteins with domain architecture numbers 1. in the genome sequence of Clostridium perfringens strain 13. BAB75463). PCC 6803 slr0222 (11. AAV45588). Spo0A combines the REC domain with an unusual HTH domain that has additional -helices (78).org/ on May 19. BAB73667). AAV44864). and all4097 (17.asm. Domain symbols are drawn approximately to scale. BAC88575). PCC 7120 all3764 (1. AAV47335). Anabaena variabilis Ava_B0191 (14. ABA24903). AAZ47577). the bacteria belonging to the orders Bacillales. AAV46418). rrnAC0075 (7. PCC 7120 all1279 (2. the sequenced strain should be unable to sporulate and produce toxins. subtilis ywpD (1. alr1968 (16. rrnAC3379 (5. In any case. 14. Nostoc sp. and NCBI protein database accession numbers for the domain architectures shown above are as follows (domain architecture number and accession number) B. AAS97149). rrnAC1626 (9. 123). namely. CAB05945) or Nostoc sp. Bradyrhizobium japonicum bll1030 (3. and Thermoanaerobacteriales (122. this HTH domain has been seen so far only in the spore-forming high-GC gram-positive bacterium Symbiobacterium thermo- .

Rhizobia. has lost some of its Mn2 -binding Asp residues (Fig. such as Deinococcus radiodurans and Clostridium acetobutylicum. coli GlnL (NtrC) response regulator. the degradation of the PP2C domain is much less pronounced. which is consistent with the absence of 54 in these Downloaded from http://jb. has been solved by the Joint Center for structural Genomics and deposited in the Protein Data Bank under accession code 1VQR. YcbB. what its role is. With the sole exception of the marine bacterium Silicibacter pomeroyi. and other members of the alpha-subdivision of proteobacteria encode an unusual response regulator that combines a C-terminal REC domain with an N-terminal sigma-24 subunit of RNA-polymerase ( E or RpoE) (Table 2). and is apparently devoid of the protein phosphatase activity. Since DNA binding by YcbB has now been experimentally demonstrated (113). S5 in the supplemental material). combines the REC-domain with the Ycf55 domain. and the only indication of their biological function(s) so far is the observation of increased expression of the C. This effect remained enigmatic until a recent study showed that YcbB controls the glutamine utilization operon (113). As noted previously (69). phototaxis. 3). Salmonella. this output domain is often encoded in the genomes of the same bacteria in a stand-alone form (see Fig. and chromatic adaptation in cyanobacteria (18. other organisms. crescentus response regulator CC3477 in the minimal medium compared to the rich medium (56). REC-HDOD. often adjacent to the gene coding for a histidine kinase of the recently described HWE family (62). Comparative analysis revealed several other clade-specific response regulators that are found exclusively in cyanobacteria (for example. This domain has been named the HD-related output domain.asm. subtilis response regulator YcbB has been originally described as one of the genes whose disruption increased cell resistance to protonophores (105). Sequence and structural analysis of this output domain (deposited in the Pfam database as domain PF08668) showed its distant relationship to the widespread HD phosphohydrolase (PF01966) domain (9).org/ on May 19. encode a response regulator with an unusual output domain. and their functions remain unknown. Several proteobacteria. However. also referred to as RssB or SprE. or HDOD. this response regulator is encoded in every alpha-proteobacterial genome that is larger than 1. phylogenetic distribution of this response regulator is limited to the gamma-proteobacterial families Enterobacteriaceae and Vibrionaceae. as it is unrelated to the E. Although the PATAN domain itself is found in a variety of bacteria. and the Hnr-related response regulators are likely to have the protein phosphatase activity (Fig. the PATANREC combination appears to be limited to cyanobacteria and -proteobacteria (83). In addition. It remains to be seen whether their RpoE-like components could function as genuine sigma subunits of the RNA polymerase. Sll1879. coli. In pseudomonads. RpoE-REC. its C-terminal domain can be considered a new type of the DNA-binding HTH domain. Sequence comparisons identified the RpoE-REC domain combination in the genome of Mesorhizobium loti (the mlr3700 gene product). 2006 DOMAIN ARCHITECTURES OF BACTERIAL RESPONSE REGULATORS 4175 philum. which is bound to cause confusion. combine the C-terminal REC domain with N-terminal PATAN (PatA N terminus) domain and an HTH domain in the middle (83). RssB. 2012 by guest . 188. The structure of one such protein. 3). these proteins can be predicted to serve as environmentally modulated transcriptional regulators. if any. brucellae. common to the spore-forming bacteria of the Firmicute lineage. whose function is unknown (154). the Slr2024 family). the current set of 390 actinobacterial response regulators does not include a single instance of a REC-SARP domain combination. coli and its closest relatives. including Vibrio cholerae and Pseudomonas aeruginosa. halobacteria (REC-HalX family). Given the DNAbinding properties of E. The availability of a complete genome sequence allows one to determine not only which proteins are encoded there but also which proteins (protein families) are missing. Response regulators of the PatA type. Campylobacter jejuni CJ0248. alpha-proteobacteria (CC0440 family). where the original genome annotation included only its Cterminal REC domain. Spo0A is a typical synapomorphy. which is currently assigned to the Actinobacteria but is apparently a member of the Firmicutes (140). Other response regulators. The Hnr-type response regulator. Actinobacteria. PatA. its output domain was previously considered to be unique (92). for example. regulates turnover of the stress sigma factor RpoS in E. or epsilon-proteobacteria (CJ1608 family). No mention of experimental studies of these response regulators could be found in the available literature. Absence of certain types of response regulators in all representatives of a given phylum could be an important feature of that phylum that might help in understanding mechanisms of signal transduction in its members.VOL. indicating that Hnr-dependent regulation of RpoS turnover is a peculiar feature of E. 80). S4 in the supplemental material). Due to the high degree of sequence conservation and narrow phyletic distribution. However. in the signal transduction phosphorelay. None of the available actinobacterial genomes encodes response regulators of the NtrC type. encode numerous transcriptional regulators of the SARP family (152). accordingly. but the lack of conservation of the key metal-binding residues of the typical HD domain did not allow us to predict whether it still has a phosphatase or phosphodiesterase activity and. sequence analysis showed that this output domain is a degraded version of the PP2C-type Ser/Thr protein phosphatase that is shorter than the typical PP2C domain. Response regulators with the RpoEREC domain combination have not been described in the available literature. which control heterocyst development. The reasons for that remain unclear. However. B. YcbB has been renamed GlnL. RssB has apparently evolved from a protein phosphatase. In fact. Thus. A cyanobacteria-specific response regulator.6 Mb. bartonellae. Avoidance of certain response regulator types. do encode response regulators with this domain combination (Table 2). which combine an HTH domain with the BTAD domain. found in a stand-alone form in chloroplasts of green plants and red algae. These observations are in line with the earlier suggestion (15) that RssB is a former anti-sigma factor that during evolution was recruited to serve as a recognition factor for proteolysis. and several other enterobacteria (53). the Cterminal domain of YcbB does not show obvious relation to any previously described HTH domain (see Fig. assigned to the COG1639 (41). the key metal-binding residues are conserved. not a protein kinase (an antisigma).

Metal-binding residues of PP2C-type protein phosphatases are shown in white . Conserved hydrophobic amino acid residues are shaded yellow. coli protein RssB (GenBank accession no. Multiple sequence alignment of the Hnr-type output domain and its comparison with the protein phosphatase domains of the PP2C family. BACTERIOL. Downloaded from http://jb.4176 GALPERIN J.asm. The top sequence is that of E. 2012 by guest FIG. other conserved residues are shown in bold typeface.org/ on May 19. AAC74317). 3.

NtrC. DISCUSSION The sequence analysis of REC domain-containing response regulators presented in this work shows that functions of these proteins are not limited to transcriptional regulation and chemotaxis. and Thiobacillus denitrificans. (DevR). Although actinobacteria encode signaling proteins with HisK. archaeal response regulators differ dramatically from bacterial ones: no sequenced archaeal genome encodes OmpR. Both depend on protein-protein interactions of the phosphorylated form REC P with its various targets but differ in the fate of the phosphoryl group. FliM (24. the remaining third consists of stand-alone REC domains.8. Finally. to the flagellar switch protein. In some cases. These data suggest that REC domains could participate in a variety of protein-protein interactions with yet unknown target proteins. There are certain deviations from the general trend: some representatives of beta-. Other archaeal response regulators include REC-PAS and REC-GAF domain combinations. In cyanobacteria. The number of response regulators encoded in each complete microbial genome shows strong positive correlation with the genome size. subtilis (Spo0F). not even the largest actinobacterial genomes encode any chemotaxis proteins. CheY P. The numbers show the positions of aligned residues and the lengths of gaps between them. or PrrA family response regulators (see Table S1 in the supplemental material.asm. Wolinella succinogenes. found. encode substantially more response regulators than other organisms with the same genome sizes. NarL. and arrows indicate the -strands. CheY-like proteins interact with a different. EAL. and ACyc output domains. Another big group of response regulators combines the REC domain with various enzymatic domains that are involved in signal transduction. 6). deltaand epsilon-proteobacteria. meaning that it is close to the quadratic function (Fig. Ser/Thr-specific protein phosphatase. 2006 DOMAIN ARCHITECTURES OF BACTERIAL RESPONSE REGULATORS 4177 genomes. This mechanism has Downloaded from http://jb. as well as a relatively low number of stand-alone REC domains. Stand-alone REC domains. In the logarithmic coordinates. resulting in a much higher fraction of DNA-binding response regulators in their set. these include the diguanylate cyclase (GGDEF). 188. 47). Another mechanism of REC-mediated signaling is the welldocumented propensity of phosphorylated REC domains to form dimers. 4) (see also reference 141). including regulation of sporulation in B. response regulators with enzymatic or protein-binding output domains. such as Geobacter sulfurreducens. heterocyst formation in Nostoc sp. still unidentified.) (Fig. whose motility apparatus is related to the type IV pili. CheC. Furthermore. and CheV family proteins. which can stay on the REC domain or be transferred to another protein with REC P functioning as an intermediate in a multicomponent phosphorelay (37). adenylate cyclase. The numbers in parentheses signify the total length of each protein. see also reference 141). While transcriptional regulators with DNA-binding output domains comprise about two-thirds of all response regulators. . chemotactic signaling by CheY involves direct binding of its phosphorylated form.VOL. The overlap between the secondary structure prediction by PSIPRED (59) and the known structures of PP2C-type protein phosphatases (32. stand-alone REC domains and response regulators with unknown output domains were not considered. The only exception is Symbiobacterium thermophilum. 27. LytR. 37). only in halobacteria or only in metanosarcinas. In most bacteria. In addition to their role in chemotaxis. As noted earlier (42). and response regulators whose output domains have not been characterized and whose functions re- main unknown. it appears that in the case of CheB. for example. this dependence shows a slope of approximately 1. other organisms encode relatively few response regulators or none at all (e. Statistics of response regulators. 149). In some cases. In archaea. GGDEF. The only response regulators that are common for bacteria and archaea are the stand-alone REC domain and CheB-like and RECHisK combinations. which have an entirely different flagellar machinery that does not include FliM. 130). 4). as well as combinations of the REC domain with uncharacterized lineage-specific domains. phosphorylation of the REC domain has been shown to activate the attached enzymatic domains (34.org/ on May 19. protein (130). 99).. none of them is found in actinobacterial response regulators. 2012 by guest letters on dark background. Besides chemotactic methylesterase CheB and protein phosphatase CheC. Archaeal transcriptional regulators and signal transducers are generally similar to those in bacteria (16. such as chemotaxis regulator CheY and sporulation regulator Spo0F. both relief of inhibition and genuine activation take place (5. While this activation could be due to the relief of enzyme inhibition by nonphosphorylated REC (34). HD-GYP. stand-alone REC domains participate in developmental processes. dramatically improving their binding to the palindromic or direct-repeat chromosomal binding sites. CheY P interacts with yet another type of switch complex (18). this includes the absence of the CheB. In a somewhat similar analysis by Ulrich and colleagues (141). cylinders indicate the -helices. Phosphorylation-induced dimerization plays a key role in the regulation of DNA-binding response regulators. only a small fraction of actinobacterial histidine kinases are hybrids. Mechanisms of REC-mediated signaling. separately expressed REC and methylesterase domains of the CheB protein have been shown to form a complex even in the absence of a linker (6). and histidine kinase output domains. and cyst cell development in Rhodospirillum centenum (17. These features illuminate the peculiarity of the signal transduction in actinobacteria and suggest that representatives of this phylum utilize a rather straightforward mechanism of signal transduction that includes tight pairing of each HisK with a cognate DNA-binding (or RNA-binding) response regulator.g. have two principal modes of transmitting regulatory signals. At the same time. REC P might function just as a sink for phosphoryl groups (10. 104) are shown above the alignment. which is not really an actinobacterium (140) (see above). c-di-GMP phosphodiesterase (EAL and HD-GYP). However. This is also the case for type IV pili-mediated social motility of Myxococcus xanthus (144). Sulfolobus spp.

and activation/relief-of-inhibition—can be expected to work in the newly described response regulators.asm. BACTERIOL. strain CBDB1. DNA-binding domains of the XRE-family. a newly described distant member of this family. However. Among the new types of DNA-binding response regulators (Table 2). these. were ignored for the calculation of the slope and the correlation coefficient of the regression line. In addition to dimerization. The interplay of dimerization and relief-of-inhibition mechanisms could be particularly important for response regulators involved in c-di-GMP turnover. Planctomycetes. yellow diamonds. The numbers in the circles indicate the data points corresponding to the following organisms: 1. and Thermotogales). 2. relief-of-inhibition. Correlation between the genome size and total number of encoded response regulators. as is the RNA-binding CsrA domain (50). Wolinella succinogenes. been demonstrated for the response regulators of the OmpR.org/ on May 19. red triangles. 155). also function as dimers. 4. This versatility of the REC domain is consistent with the diversity of signal output domains that interact with it. the overall activity of such response regulators changes from c-diGMP-hydrolase to c-di-GMP synthetase and vice versa. and HxlR types are known to function as dimers (25. It is entirely possible that upon phosphorylation of their REC domains. 137) appears to be due to the relief-of-inhibition mechanism. Dehalococcoides sp. which comprise 1. 94). open squares. The same regulatory mechanisms mentioned above—dimerization. Dechloromonas aromatica. for example. Therefore. In the response regulators of the NtrC family. phosphorylation of the REC domain activates the diguanylate cyclase by enabling formation of a GGDEF dimer. 2012 by guest FIG. 112). all three domains appear to participate in oligomerization. Spirochetes. protein-protein interaction. 5. MerR.1% of all response regulators in the analyzed set. beta-. Such response regulators should have the only the phosphodiesterase activity in their monomeric form but might acquire diguanylate cyclase activity upon dimerization. In response regulators of the REC-GGDEF type. REC-mediated signaling might involve other mechanisms. 4. cyan circles. New types of response regulators. Sulfolobus solfataricus. Bacteroidetes. black circles. the active form of the enzyme (99. brown diamonds. Downloaded from http://jb. and PrrA families (12. 93. direct activation. DNA-binding domains of LysR. 88. which regulates the activity of its AAA ATPase domain (67. Geobacter sulfurreducens. which includes cI and Cro regulators. the RpoE-like domain of the . and epsilon-proteobacteria. blue squares. however. Chlamydiae. the c-di-GMP-specific phosphodiesterase (the EAL domain) is active as a monomer (114). Deinococcus-Thermus. Each symbol indicates the logarithm of the number of response regulators encoded in a single bacterial genome with the following color scheme: actinobacteria. Archaeal response regulators are indicated by yellow triangles. 73. LytR. 3. NarL.4178 GALPERIN J. Organisms that encode no response regulators are indicated by symbols on the x axis (logN 0). and protein-protein interactions with or without phosphoryl transfer. 76). would function the same way. gamma-proteobacteria. alpha-proteobacteria. delta-. members of other bacterial phyla (Aquificales. activation of EAL phosphodiesterase by REC phosphorylation in response regulators of the REC-EAL type (131. such as. firmicutes. In contrast. allosteric regulation of the output domains. there are some without obvious deviations from the consensus (109). cyanobacteria. Although in many such proteins either the GGDEF or EAL domain appears to be inactivated (114). suggesting that the BetR domain. This distinction is particularly important for the response regulators of REC-GGDEFEAL domain architecture.

often found in transmembrane receptors (42). R. P. and RsbW-type Ser/Thr protein kinases (anti-sigma factors) are known to function as dimers (19. However. 1 and Tables 1 and 2). previously uncharacterized rare or unique domains identified in this study are listed in the supplemental material and will soon be available in the public domain databases. Igor Zhulin. that inhabit relatively stable and unique environments where few parameters. Paul. far fewer numbers of the LytRtype.org/ on May 19. Plant pathogen Leifsonia xyli encodes a unique response regulator with the LmbE output domain. In all other cases. just as in CheB. In general. and Yuri Wolf for helpful advice. Microbiol. Tao Tao. depending on the environmental conditions. Downloaded from http://jb.S. 4) and the total number of encoded proteins. Aldridge. An experimental study of these novel response regulators and analysis of their potential functions will remain the task for future work. as well as an allosteric regulation. a clear deviation from the standard REC-HTH architecture. and epsilon-proteobacteria that have been previously found to encode more signaling proteins than others with the same genome size (42). allowing modulation of the cellular levels of cAMP and c-di-GMP. and response regulator proteins than other prokaryotes with the same genome size. As discussed above. Darren Natale. 141. Several relatively common. Cell cycle-dependent degradation of a flagellar motor component requires a novel-type response regulator. These are typically obligate parasites. 2003. it appears that fusing an existing metabolic enzyme to the REC domain is an evolutionarily harmless procedure: the resulting fused protein is inactive unless its REC domain is phosphorylated by a cognate histidine kinase. and it is not known if they are ever expressed. REFERENCES 1. Given only a minimal overlap between the two data sets. Indeed. Bill Klimke. Most enzymatic output domains found in response regulators (Tables 1 and 2) are signal transduction domains themselves. This domain combination has been found in several actinobacteria and cyanobacteria and in Solibacter usitatus.asm.VOL. 142). and YesN-type response regulators. P. 68. Microbiol. 156). as well as the activity of Ser/Thr protein kinases and phosphatases. 2012 by guest . The census of response regulators confirmed several trends seen previously in the census of signal transduction proteins (42). 188. recently shown to have Nacetylglucosamine deacetylase activity (Table 2). this is probably correct. Aldridge. histidine kinases. Fusions with other enzymes typically have a narrow phylogenetic distribution. also remains a possibility. Among enzymatic output domains of response regulators (Tables 1 and 2). such as lignin and chitosan. This study was supported by the Intramural Research Program of the National Library of Medicine at the U. The largest deviation from the general trend is seen in the same representatives of beta-. ligand-binding. Phylogenetic distribution of response regulators. Rainey. the total number of response regulators encoded in completely sequenced prokaryotic genomes positively correlates with the genome size (Fig. Remarkably. signal transduction. Goymer. and U. In these response regulators. This diversity makes it even more difficult to explain the predominance of OmpR-type and NarL-type response regulators. Such combinations must have arisen from random gene translocation and fusion events and were later fixed in evolution because they allowed tight regulation of the enzyme activity. P. see Table S1 in the supplemental material) supports the view that signaling domain fusions follow the Lego principle: almost any fusion can occur but only some of them remain fixed in the evolution (43). or organisms such as Sulfolobus spp. adenylate and diguanylate cyclases. a recently sequenced representative of the phylum Acidobacteria. Mol. PrrA-type. Such domain combination could allow this bacterium to regulate degradation of N-acetylglucosamine-containing plant polymers. 1999. and two reviewers for critical comments. these observations show that certain environmental bacteria encode a disproportionately higher number of sensor. which will provide further understanding of the organization and evolution of the prokaryotic signal transduction systems. For DNA-binding domains. 47:1695–1708. delta-. The diversity of output domains in response regulators (Tables 1 and 2) suggests that virtually any DNA-binding or enzymatic domain could be fused to the REC domain to form a response regulator. ever change. 2006 DOMAIN ARCHITECTURES OF BACTERIAL RESPONSE REGULATORS 4179 CC3477-type (RpoE-REC) response regulators is not known to form dimers. Role of the GGDEF regulator PleD in polar development of Caulobacter crescentus. many more types of response regulators can be expected to be found in microbial genomes. 2. if any. The same logic could be applied to the fusions between REC domains and other signaling. by sensory histidine kinases in response to specific environmental cues (41). HTH domains such as LysR or MerR that are typically localized at the N-termini of the corresponding transcriptional regulators have the same position in response regulators (Table 2). Origin and function of diverse domain architectures. and many other colleagues for suggestions. as representatives of all major classes of the HTH domain (8) could be found in response regulators (Table 2). or protein-binding domains. and U. In accordance with previous observations (46. both phosphorylation-induced dimerization of the REC domains and relief-of-inhibition could contribute to the activity of the output domains. Such fusions add yet another layer of regulation in the complex intracellular signal transduction network. a direct enzyme activation by REC P. National Institutes of Health. 32:379–391. and only sporadic appearance of the response regulators with other types of the HTH domain (Fig. the large number of rare domain fusions (Table 2. On the other end of the spectrum are bacteria and archaea that encode fewer response regulators than the average bacterium of the same genome size. so they most likely act through relief of inhibition and/or protein-protein interactions of their C-terminal REC domains. Jenal. In one such case. a nonphosphorylated REC domain can be expected to block enzyme activity the same way it does that in the CheB structure (34). P. 82. Mol. the propensity of the REC domain to dimerize upon phosphorylation offers an effective mechanism of transcriptional regulation. These data validate the use of the term “bacterial IQ” (42) to describe the fraction of the bacterial proteome dedicated to environmental sensing and signal transduction. or Thermoplasma spp. such as Yersinia pestis.. Mark Gomelsky.. Jenal. If this logic is correct. 28. ACKNOWLEDGMENTS I thank Andrei Gabrielian. a fusion of the REC and thioredoxin reductase domains could play an important role in environmental regulation of the cellular dithiol-disulfide ratio.

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