Center for Information Biology and DDBJ, National Institute of Genetics, Mishima, Japan
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Abstract |
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Key Words: parallel evolution repressor periplasmic binding protein operon functional genomics ABC transporter
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Introduction |
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The crystal structures of three members of the LacI/GalR family, PurR (purine nucleotide synthesis repressor), LacI (lactose operon repressor), and TreR (trehalose operon repressor), clearly show that the LacI/GalR family repressors have two structural domains (Schumacher et al. 1994a; Friedman, Fischmann, and Steitz 1995; Lewis et al. 1996; Hars et al. 1998). The N-terminal domain is a helix-turn-helix DNA-binding domain, and the C-terminal domain is a ligand-binding domain whose 3D structure is similar to those of periplasmic binding proteins (PBPs), as shown in figure 1. The C-terminal domain is especially similar to the PBPs that bind sugars (Fukami-Kobayashi, Tateno, and Nishikawa 1999). It also shows a weak sequence homology to the PBPs (Mauzy and Hermodson 1992). It has thus been suggested that the C-terminal domain of the repressors and the PBPs share a common ancestor, and that the progenitor repressor was formed when the common ancestor acquired the DNA-binding domain in its N-terminal.
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Each repressor has its own ligand specificity, and so does each PBP. Some repressors and PBPs share the same ligand specificity. For instance, GalS (repressor, R) and MglB (PBP, P) both bind D-galactose/D-glucose; XylR (R) and XylF (P) bind D-xylose; and RbsR (R) and RbsB (P) bind D-ribose (Bairoch and Apweiler 2000). Such pairs, made up of a repressor and a PBP, are often encoded in a single operon in the Escherichia coli and Bacillus subtilis genomes (Itoh et al. 1999). Similar operon structures have been suggested to be present in other bacterial species (Tomii and Kanehisa 1998).
The question that then arises is, which occurred to the common ancestor first, acquisition of the DNA-binding domain or divergence of ligand specificity? If the acquisition of the DNA-binding domain occurred first, then only one acquisition is enough to generate the repressor family. That possibility is consistent with the results of phylogenetic analysis of several protein families that show domain organization was established in an early stage of their evolution (Fukami-Kobayashi, Tomoda, and Go 1993; Fukami-Kobayashi et al. 1996; Koyanagi et al. 1998). On the one hand, if this is the case, then ligand specificity must have evolved in the LacI/GalR family and in the PBP family independently, even if a pair of repressor and PBP is coded in the same operon. On the other hand, if the divergence of ligand specificity occurred first, then the ligand specificity must have been unchanged while the ancestral PBP gene duplicated and one of the duplicates acquired the DNA-binding domain to evolve into a repressor. This process would explain why a pair of repressor and PBP with the same ligand specificity is often encoded in a single operon. In the latter case, however, we have to assume that the acquisition of the DNA-binding domain occurred independently in each operon.
It has been reported that sequence similarity of the N-terminal DNA-binding domain is higher than that of the C-terminal ligandbinding domain in the LacI/GalR family (Weickert and Adhya 1992; Nguyen and Saier 1995). This conclusion implies that the functional divergence of ancestral PBPs took place prior to the acquisition of the N-terminal domain. In addition, the number of LacI/GalR repressors varies widely among bacterial species (Kawabata et al. 2002), indicating that the acquisition of the DNA-binding domain occurred independently to produce a repressor unique to each lineage.
When bacteria needed a repressor with novel ligand specificity, which of the above-mentioned two strategies did they employ? Did they make the repressor from an existing repressor by inventing the novel specificity, or from PBP by acquiring the DNA-binding domain? Because this problem is rooted in the acquisition of a new protein function, its solution will contribute to the prediction of unknown function of open reading frames (ORFs) identified in genome sequences. In this paper we report our approach to solving this problem.
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Materials and Methods |
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The Database GTOP
To collect data on the repressors and their PBP homologues, we used the database GTOP (Genes TO Proteins, http://spock.genes.nig.ac.jp/genome/gtop.html) (Kawabata et al. 2002) of December 2000. GTOP contains the results of various sequence analyses of all ORFs of the organisms for which the whole genome sequence has been reported. It particularly features an extensive utilization of protein 3D-structure information. The 3D structures of the ORFs have been predicted by PSI-BLAST (Altschul et al. 1997) search against PDB (Berman et al. 2000) in GTOP. The predicted 3D-structures are classified into categories according to the criterion of SCOP (Murzin et al. 1995). We also used GTOP for predicting the function of the ORF and the operon structure.
Sequence Data Collection
The C-terminal domains of the LacI/GalR family repressors are classified into "purine repressor (PurR) C-terminal domain," "lac-repressor (lacR) core C-terminal domain," and "trehalose repressor C-terminal domain" in SCOP. Our previous study (Fukami-Kobayashi, Tateno, and Nishikawa 1999) indicated that their closest PBP homologues are classified into "D-ribosebinding protein," "L-arabinose-binding protein," "D-allosebinding protein," and "galactose/glucose-binding protein." Those seven groups belong to "L-arabinosebinding protein-like" family (its hierarchy position is a/b class, periplasmic binding protein-like I fold, periplasmic binding protein-like I superfamily in SCOP). From GTOP, we selected the ORFs whose predicted 3D structures are classified into any of the seven groups.
Multiple Alignment
Some of the selected ORFs have a predicted all-alpha region in addition to the PBP-related sequence. When we made multiple alignments of the translated amino acid sequences from the ORFs, we removed the all-alpha regions for better alignment in the common region to all the ORFs.
We used ClustalW 1.81 (Thompson, Higgins, and Gibson 1994) and PRRN (Gotoh 1999) with the default parameters for multiple alignments of the amino acid sequences. To examine the performance of the two computer tools, we determined the spatially equivalent secondary structures by MATRAS (Kawabata and Nishikawa 2000) beforehand. The proteins and their PDB data subjected to the MATRAS determination were treR_Eco (1BYK chain A [Hars et al. 1998]), purR_Eco (1QPZ chain A [Glasfeld et al. 1999]), yjcX_Eco (1RPJ [Chaudhuri et al. 1999]), lacI_Eco (1TLF chain A [Friedman, Fischmann, and Steitz 1995]), rbsB_Eco (2DRI [Bjorkman et al. 1994]), mglB_Eco (2GBP [Vyas, Vyas, and Quiocho 1988]), and araF_Eco (8ABP [Vermersch et al. 1991]), which were selected from each of the seven SCOP groups by their resolution, R-factor, and source.
Construction of a Phylogenetic Tree
Using the result of the alignments, we constructed maximum likelihood (ML) trees by ProtML in MOLPHY (Adachi and Hasegawa 1996). A column of aligned sites that has one or more gaps was omitted from the tree construction. We adopted the JTT model (Jones, Taylor, and Thornton 1992) to compute the likelihood of a tree. First, 50 seed trees were generated by the quick add OTUs search mode of ProtML. Then, a tree with a larger likelihood value was searched by rearranging a part of the topology of a seed tree. After repeating this procedure for all seed trees, the tree with the largest likelihood value among the results was chosen as the ML tree. Reliability of each internal branch of the tree was then evaluated by the bootstrap probability (Felsenstein 1985), which was computed by the "resembling of estimated log-likelihood" (RELL) method (Hasegawa and Kishino 1994).
Identification of Ligand-Binding Sites in PBPs
We adopted the ligand-binding sites that have been identified by HBPLUS (McDonald and Thornton 1994) in the PDBsum database (Laskowski 2001). The PDB entries adopted were 1QPZ chain A (purine-binding sites), 1TLF chain A (lactose-binding sites), 2DRI (D-ribosebinding sites), 2GBP (D-galactose/D-glucosebinding sites), and 8ABP (L-arabinosebinding sites).
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Results |
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The ML tree was finally constructed using the ClustalW result (fig. 2). The LacI/GalR type repressors in magenta made one cluster containing the XylR type repressors (shown in green). Note that the bootstrap probability of the branch that divides the cluster from the others is 98%. We also constructed another ML tree using the PRRN result, which again shows that all the repressors are clustered together at the bootstrap probability of 100%. The tree is also available at http://spock.genes.nig.ac.jp/kfukami/LGF/supplement/.
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Repressors and PBPs Acquired Their Ligand-Binding Sites Independently
There are pairs of PBP and repressor sharing the same ligand in the 102 ORFs selected (Bairoch and Apweiler 2000). The pairs are listed in table 2. In our analysis, we could deduce the ligands of two repressors VC2337 and TM0949 as D-galactose/D-glucose and D-ribose, respectively. The repressors and PBPs in table 2 are circled in color in figure 2 according to their ligand specificity as shown in the phylogenetic tree. Because the repressors and the PBPs are present in different clusters in the tree, the two must have acquired their ligand specificity independently, as illustrated in figure 3.
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In addition, the phylogenetic tree shows that the acquisition of specificity for ligands such as D-galactose/D-glucose and D-ribose might have occurred more than once within the repressor or PBP family. For example, because the D-galactose/D-glucosebinding protein from Treponema pallidum (TP0684) is not clustered with those of other species, T. pallidum probably acquired the ligand specificity independently. The phylogenetic tree also indicates that the ribose operon repressors have evolved in four lineages; the first to Escherichia coli, Vibrio cholerae, and Haemophilus influenzae, the second to Pseudomonas aeruginosa, the third to B. subtilis and B. halodurans, and the fourth to T. pallidum. As for the PBPs for D-ribose, it is not clear whether the acquisition occurred once or more, because of the low bootstrap probability (48%) of the branch that divides the ribose-binding protein of P. aeruginosa (rbsB_Pae) from the others.
Figure 4 shows multiple alignments in three regions including ligand-binding sites of three sets of the amino acid sequences. The upper set refers to ribose-binding proteins and ribose operon repressors, the middle set to repressors of known 3D structure and the lower set to repressors and binding proteins for D-galactose/D-glucose. The ligand-binding sites are known in rbsB_Eco, purR_Eco, lacI_Eco, treR_Eco, and mglB_Eco from their crystal structure. They are enclosed in a red box in the alignments in figure 4. Although overall amino acid similarity is higher within each of the PBPs and the repressors than between them as shown in the tree, the similarity of the ligand-binding sites alone is higher between the PBP and the repressor sharing the same ligand than within each PBP and repressor pair. For example, in figure 4 all ribose-binding proteins and ribose operon repressors have asparagine (N) at site 54, whereas the proteins for D-galactose/D-glucose, except TP0684, have aspartic acid (D) at that site. Most proteins for D-ribose have DR/DW at sites 134135 or nearby, whereas the proteins for D-galactose/D-glucose have NR/NK. All proteins for D-galactose/D-glucose, except TP0684, have aspartic acid (D) at site 198. The aligned residues indicate that the PBP and the repressor independently acquired the same or a similar amino acid at their binding sites by homoplasious replacement to bind the same ligand, even if the pair is located in the same operon.
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Discussion |
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The regulatory mechanism of DNA binding is also consistent with our finding. The mechanisms of LacI and PurR are very similar to each other: they use a hinge helix for DNA binding, as well as the helix-turn-helix structure (Schumacher et al. 1994a, 1994b; Nagadoi et al. 1995; Bell and Lewis 2000). The hinge helix is formed in the presence of DNA in a region between the helix-turn-helix structure of the DNA-binding domain and the ligand-binding domain. Although the helix-turn-helix structure and recognition of the DNA major groove by the structure are found in other DNA-binding protein families, recognition of the DNA minor groove by the hinge helix is unique to the LacI/GalR family. The residues in the hinge helix play a crucial role in DNA binding of the repressors (Choi and Zalkin 1994; Pace et al. 1997). Even insertion of one glycine between the hinge region and the ligand domain causes a 100-fold decrease in the affinity of the lactose repressor for its target DNA sequence (Falcon and Matthews 1999). In addition, the repressor functions as a dimer/tetramer, where the DNA binding is regulated by interactions not only between the two domains in one subunit but also between subunits. These findings together suggest that the regulatory mechanism is so elaborated that it is hardly possible that such a system was repeatedly formed in evolution. This suggestion is in agreement with our result that the LacI/GalR family is a monophyly.
Homoplasy of Binding Specificity
The phylogenetic tree, in contrast to the above monophyly, indicates that the ligand specificity did evolve more than once in both the PBP and the LacI/GalR families. Such a homoplasy is probable. The crystal structures of these families show that the number of the ligand-binding sites is no more than 20 (Laskowski 2001), which corresponds to only a small percentage of the total number of sites. In addition, ligand specificity is determined only by a few of them: the same residue is conserved at several ligand-binding sites regardless of the specificities. As shown in the multiple alignments in figure 4, ligand specificity can be acquired by replacement with the corresponding residue at a small number of sites. It is thus probable that parallel replacements at such limited sites occurred in evolution. In fact, convergent evolution by amino acid replacements at specific sites of a protein has already been observed in lysozyme (Stewart, Schilling, and Wilson 1987; Kornegay, Schilling, and Wilson 1994), color vision pigment (Yokoyama and Yokoyama 1990; Briscoe 2000), and blood group antigens (O'hUigin, Sato, and Klein 1997; Kitano et al. 2000; Sumiyama et al. 2000). It is expected that site-specific mutagenesis experiments in the ligand-binding sites will verify our prediction.
We consider that the homoplasy at the ligand-binding sites was evolutionarily fixed by selection, not just by chance. It is observed that genes in an operon have related functions. For example, PBP, a repressor, and other genes in an operon have related function for the same ligand (Tomii and Kanehisa 1998; Itoh et al. 1999). Most pairs of PBP and repressor genes sharing the same ligand are located in the "vicinity, as shown in table 2. In addition, the vicinity cannot be explained by a historical event that the ancestral operon possessed the same operon structure. Gene members and their order are not always the same in orthologous operons, which implies gene rearrangement in the operons in evolution. Nevertheless those operons have kept the genes with related functions together. These observations suggest that it is advantageous for those genes to be in the same operon, and that PBP and a repressor in the same operon are under constraint to have the same ligand specificity.
While ligand specificity of the PBP and the LacI/GalR families evolved from different origins, ligand-binding domains evolved from their common ancestor. Convergent evolution of protein functions is common, whereas that of protein structure is rare (Doolittle 1994). It is thus unlikely that the ligand-binding domains in the two families evolved independently into the same 3D structure. In addition, there is little functional necessity for those domains to assume the same structure. Functional homoplasy is often brought about by different mechanisms. For example, different molecules, heme and a pair of copper ions, are involved in oxygen binding of hemoglobin and hemocyanin, respectively. Even the same catalytic mechanism is derived from different origins. The catalytic triad of serine protease has evolved at least three times, as evidenced by subtilisin, trypsin, and alpha/beta hydrolase fold enzyme (Ollis et al. 1992). It is certain that these enzymes have different origins, because they have different protein folds and different sequence arrangements in the catalytic triad. In particular, the catalytic triad of the alpha/beta hydrolase fold enzyme is a "mirror image" of that of serine protease. Thus, there is often more than one solution to a biochemical problem. In the case of the PBP and repressor, for example, the same ligand specificity would have evolved from different protein folds and/or different binding modes even if those proteins had not shared a homologous domain. In fact, the ligand-binding domains of the two proteins do have the same protein fold, and they probably have the same binding mode as well, because the same residues at the structurally equivalent sites seem to be involved with the binding for the same ligand between the two proteins.
Origin and Evolution of Operon Structures of PBPs
It is reported that PBP is often encoded in an operon not only with repressor but also with permease and ABC protein that cooperate with their partner PBP in transportation of ligand (Tomii and Kanehisa 1998; Itoh et al. 1999). This suggests the following model on the origin and evolution of an operon containing those protein genes: First there were ancient operons encoding three genes of PBP, permease, and ABC protein that functioned for the same ligand. Then a PBP gene in one of the ancient operons duplicated, and one of those duplicates acquired a DNA-binding domain in the 5' end. This operon amplified next in genome, and diverged to those with a variety of ligand specificities.
In this model, the order of the four genes in the operon is expected to be the same among the descendants. However, as mentioned in the previous section, the order has been conserved only among the orthologous operons of closely related species, and the gene members are not always the same among the descendants. It is thus considered likely that the operon occasionally rearranged the gene order in itself, translocated a gene outside, or acquired a gene with a related function into itself, while it amplified in the genome and acquired new ligand specificities. Such gene context conservation has also been found in glutamate ABC transporter genes, translation-associated genes, and flagellum-related genes (Lathe, Snel, and Bork 2000). If this is the case, we need to impose the evolutionary constraint that would have kept the functionally related genes in an operon. This imposition should be reasonable, because it is expected to be advantageous for the functionally related genes to be encoded together in a cotranscribed and so coregulated unit.
The results of this study demonstrate that the LacI/GalR and the PBP families can be distinguished by analyzing their overall structure, whereas their ligand specificities are determined mainly by the ligand-binding sites. The sites are a limited number of residues and compose local structure of a protein. Our finding suggests that it is more effective to consider spatial arrangement of functionally important residues than to compare overall similarity when we attempt the empirical prediction of unknown protein function in functional genomics.
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Acknowledgements |
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Footnotes |
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Naruya Saitou, Associate Editor
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