Bioinformatics Advance Access originally published online on April 6, 2005
Bioinformatics 2005 21(12):2805-2811; doi:10.1093/bioinformatics/bti418
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MEDS and PocR are novel domains with a predicted role in sensing simple hydrocarbon derivatives in prokaryotic signal transduction systems
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health Bethesda, MD 20894, USA
*To whom correspondence should be addressed.
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONSYSTEMS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
|---|
We identify two conserved domains in diverse bacterial and archaeal signaling proteins. One of them, the MEDS domain, is typified by the DmcR protein from Methylococcus and the other by the PocR protein of Salmonella typhi. We provide evidence that both these domains are likely to sense simple hydrocarbon derivatives and transduce downstream signals on binding these ligands. The PocR ligand-binding domain is shown to contain a novel variant of the fold found in PAS and GAF domains. The MEDS domain is present in both methylotrophs and complex methanogens, and both the MEDS and PocR domains show a lineage-specific expansion in the latter organisms, suggesting a role in sensing their principle growth substrates. The MEDS domain is also found in the negative regulators of the sigma factor SigB in actinomycetes, including pathogens like Mycobacterium tuberculosis. Hence it is possible that these sigma factors, involved in aerial mycelium development and stress response in the actinomycetes, might be under the regulation of as yet uncharacterized small molecules.
Contact: aravind{at}ncbi.nlm.nih.gov
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONSYSTEMS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
|---|
The genomic revolution has fueled nearly a decade of comparative sequence and structure analyses of prokaryotic signaling proteins, which have helped in uncovering several basic structural, functional and mechanistic features of these systems. The principal paradigm emerging from these studies has been the recruitment of a relatively small set of domains that bind small molecule ligands as stimulus sensors or allosteric regulators in most prokaryotic signaling systems (Anantharaman et al., 2001; Taylor and Zhulin, 1999; Taylor et al., 1999). These small molecule-binding domains (SMBDs) are typically covalently linked in the same polypeptide to diverse catalytic domains, such as histidine and serine/threonine kinases, receiver domains, nucleotide cyclases, diguanylate cyclases and cyclic nucleotide phosphodiesterases, or to non-catalytic regulatory domains such as the DNA-binding helix-turn-helix (HTH) domains, methyl-accepting chemotactic receptor domains and membrane-spanning channel or transporter domains (Anantharaman et al., 2001; Pao and Saier, 1995). The SMBDs bind environmental and intra-cellular ligands and appear to transmit the conformational change caused by this interaction to the other associated signaling domains, and thereby regulate their biochemical activities. The most prominent intracellular SMBDs that are seen in most prokaryotic signaling contexts are the PAS domains that bind diverse ligands, including flavin, which allow them to sense light and redox potential, the GAF domains that are prominent sensors of cyclic nucleotides and the CBS domains that might also sense purine derivatives (Aravind and Ponting, 1997; Bateman, 1997; Ponting, 1997; Ponting and Aravind, 1997; Taylor and Zhulin, 1999). Cell surface receptors in prokaryotes also have several distinctive ligand-binding domains such as the periplasmic binding proteins domains (PBP-I and PBP-II, which also function in intracellular contexts), the CACHE and the CHASE domains (Anantharaman and Aravind, 2000, 2001; Mougel and Zhulin, 2001; Tam and Saier, 1993; Tyrrell et al., 1997; Vartak et al., 1991). Many of these prokaryote-type ligand-sensing mechanisms are also utilized in eukaryotes, especially in the context of photoreception, neurotransmission in animals and hormone response in plants (Aravind et al., 2003).
In addition to the above-mentioned frequently occurring SMBDs, there are several less prevalent SMBDs that occur at lower frequencies in several prokaryotic signaling contexts. The identification of these domains is aided by the explosion in genome sequence data from increasingly diverse lineages of bacteria. Characterization of such domains might help in better understanding the structural diversity of protein scaffolds which are utilized in specific sensing of low-molecular-weight compounds and also point to hitherto unstudied sensory mechanisms in prokaryotes. Such understanding could in turn lead to new leads regarding the biology of complex human pathogens and engineering of bio-sensors that might recognize and respond to a diverse repertoire of small molecules.
In this work, we report a novel, predicted ligand-binding domain that is present in several archaeal and bacterial signaling proteins, and a novel variant of the PAS–GAF fold, both of which we predict to function in similar signaling contexts.
|
SYSTEMS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONSYSTEMS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
|---|
The non-redundant (NR) database of protein sequences (National Center for Biotechnology Information, NIH, Bethesda, MD) was searched using the BLASTP and PSI-BLAST programs (Altschul et al., 1997). Profile searches using the PSI-BLAST program were conducted either with a single sequence or an alignment used as the query, with a profile inclusion expectation (E) value threshold of 0.01, and were iterated until convergence (Aravind and Koonin, 1999). Multiple alignments were constructed using the T_Coffee program (Notredame et al., 2000), followed by manual correction based on the PSI-BLAST results. Protein secondary structure was predicted using a multiple alignment as the input for the JPRED and PHD programs (Cuff and Barton, 2000; Rost and Sander, 1993). Preliminary clustering of proteins was done using the BLASTCLUST program with empirically determined length and score threshold cut off values (for documentation see ftp://ftp.ncbi.nih.gov/blast/documents/README.bcl). Previously known, conserved domains were identified using PSI-BLAST derived profiles for them, with the RPS-BLAST program (Marchler-Bauer et al., 2003) (http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi). Sequence-structure threading was performed using the 3DPSSM server (http://www.sbg.bio.ic.ac.uk/~3dpssm/). Gene neighborhoods were obtained by isolating all conserved genes, in the neighborhood of the gene under consideration that showed a separation of <70 nucleotides between their termini. Genes fulfilling this criterion and occurring in the same direction were considered likely to form operons. Gene neighborhoods were determined by searching the NCBI PTT tables (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome) with a script custom-written by the authors.
|
RESULTS AND DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONSYSTEMS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
|---|
Characterization of the MEDS domain
As a part of an effort to identify potential domains that might be involved in sensing novel environmental small molecules, we examined several prokaryotic one-component and two-component signaling systems. The DcmR protein from methylotrophic bacterium, Methylobacterium sp. strain DM4, is a repressor that negatively regulates the expression of the DcmA (dichloromethane dehalogenase). In the presence of dichloromethane as the sole carbon and energy source, DcmR dissociates from the promoter of the DcmA, and allows utilization of the metabolite by means of the dichloromethane dehalogenase (Kayser et al., 2002; La Roche and Leisinger, 1991). DcmR is the sole regulatory protein required for dichloromethane responsiveness in Methylobacterium, and it contains an N-terminal HTH domain (La Roche and Leisinger, 1991) combined with an uncharacterized C-terminal globular domain. Combinations of the HTH domain with a variety of ligand-binding domains, either to the N-terminus or C-terminus within the same polypeptide, is seen in numerous one-component transcription factors, such as AraC, LacI and Crp (Anantharaman et al., 2001). Based on the analogy to these domain architectures, we propose that the C-terminal domain of DcmR binds dichloromethane. In order to investigate further the affinities and distribution of this domain, we conducted an iterative sequence profile search with the C-terminal region of DcmR (Genbank gi: 95275; Fig. 1) of the NR database using the PSI-BLAST program (profile inclusion threshold = 0.01; iterated till convergence with statistical correction for compositional bias). Prior to convergence, the search recovered numerous proteins from the methanogenenic archaeal genus Methanosarcina (e.g. MA1270 from Methanosarcina acetivorans, Meth020011 from M.barkeri and MM0948 from M.mazei; E-values = 10–4–10–12 in iteration 1) and another methylotrophic bacterium Methylococcus capsulatus (MCA2071, 10–7 iteration 3). Transitive searches with the corresponding region from these proteins additionally recovered related regions in proteins from several other bacteria such as Mycobacterium, Nocardia, Streptomyces (anti-sigma factor PrsR/RsbA) and Burkholderia (Fig. 1) with statistically significant E-values (E = 10–4–0.003). Reciprocal searches seeded with most of these newly obtained proteins consistently recovered a similar group of proteins, including DcmR, demonstrating the absence of potential false positives. These observations suggested that the conserved region shared by DcmR and the above proteins defines a novel domain, and we accordingly termed it the MEDS (methanogen/methylotroph, DcmR sensory) domain.
|
A multiple alignment of the MEDS domain was prepared using the T_Coffee program (Notredame et al., 2000) and this was in turn used to predict its secondary structure using the Jpred2 program (Cuff and Barton, 2000). The predicted structure suggests the presence of a globular
/ß fold with six regularly repeating strand-helix units. This secondary structure pattern does not match any of the currently characterized SMBDs. The PBP-I and PBP-II domain families contain two distinct /ß structural units, each with a flavodoxin-like topology and 5–6 strand-helix elements (Tam and Saier, 1993; Tyrrell et al., 1997). However, given that the average length of the MEDS domain corresponds to only a single flavodoxin-like unit, it is unlikely to form a dyad structure similar to the PBP-I/II domains. The multiple alignment of the MEDS domain indicates that it contains a well-conserved histidine at the beginning of strand-1, an acidic residue at the beginning of strand-2, an arginine at the beginning of strand-4 and a histidine at the beginning of strand-6 (Fig. 1). The conserved histidine residues in particular may form the site for the attachment of a prosthetic group. Additionally, a conserved cysteine residue at the end of strand-5 is predicted to lie on the surface opposite to the remaining conserved residues. It is possible that it also serves as a second site for attachment of a prosthetic group.
Domain architectures of the MEDS domain proteins and the identification of a conserved domain containing a novel variant of the PAS–GAF fold
A systematic analysis of the proteins containing the MEDS domain revealed the presence of several distinct domain architectures in addition to the fusion to the HTH domain that is seen in DcmR (Fig. 2). There were solo occurrences (e.g. MCA2071 from Methylococcus), direct fusions to the histidine kinase domain (e.g. the actinomycete proteins like PrsR) and indirect combinations with histidine kinases along with multiple intervening PAS and GAF domains (Fig. 2). An examination of the predicted operons with genes encoding MEDS domain proteins showed that they typically co-occur with genes for other signaling proteins, such as those with receiver domains, other histidine kinase proteins, anti-sigma factors and HD-GYP-type diguanylate phosphodiesterase domains. These architectures and predicted operon organizations suggest that the MEDS domain proteins are part of signaling cascades that function through two-component phospho-relay, phosphorylation or diguanylate-dependent mechanisms to transmit signals arising from ligands bound by the MEDS domain.
|
Interestingly, several of the MEDS domain-histidine kinase proteins from the archaeal genus Methanosarcina, showed an additional novel conserved region sandwiched between the C-terminus of the MEDS domain and the downstream PAS domains (e.g. in MA4090 from M.acetivorans, Fig. 2). Iterative sequence-profile searches with PSI-BLAST seeded with this region recovered related segments in several Methanosarcina proteins and additionally in several proteins from bacteria such as Enterococcus, Salmonella, Listeria, Clostridium/Moorella, Geobacter and Myxococcus with statistically significant e-values. For example, a search seeded with the MA4090 protein against the NR database recovered the PocR protein from S.typhi (Bobik et al., 1992; Rondon and Escalante-Semerena, 1996) with E = 10–6 in iteration 3 and the DhaS protein from Clostridium butyricum (Raynaud et al., 2003) with E = 10–5 in iteration 4. This region of sequence similarity shared by the above proteins corresponded to the region of sequence similarity that has been reported in two 1,3-propanediol sensing regulatory proteins, namely PocR and DhaS (Raynaud et al., 2003). In the former protein it occurs fused to a DNA-binding HTH domain of the AraC family and in the latter protein to a histidine kinase. These observations suggested that this segment defines yet another domain (hereinafter referred to as the PocR domain) with a role in sensing small molecules, such as 1,3-propanediol. In addition to co-occurring with the MEDS domain in several Methanosarcina proteins, the PocR domain displays several independent architectures. It occurs in combination with different HTH, histidine kinase, GGDEF-type diguanylate cyclase, HD-GYP-type diguanylate phosphodiesterase, methyl-accepting chemotactic receptor and NtrC-like ATPase domains suggesting that it is utilized as a ligand-binding regulator in a range of signaling pathways (Fig. 2).
A multiple-alignment-based secondary structure prediction for the PocR domain (Fig. 3) revealed the presence of a globular –ß fold with a progression of secondary structure elements congruent to the fold present in the PAS and GAF domains ["profilin-like fold" in the SCOP database (Lo Conte et al., 2002)]. To further explore this connection, we carried out sequence-structure threading of the PDB database with different PocR queries using the 3D-PSSM (http://www.sbg.bio.ic.ac.uk/~3dpssm/) and combined-fold prediction methods (Fischer, 2000). Both these methods recovered structures of PAS domains (1ew0/1drm, PAS domains from the FixL from Rhizobia; 1byw PAS domain of the ERG potassium channels with 80–90% confidence for possessing identical fold as hit in 3DPSSM) or profilin (1acf; Acanthamoeba profilin; score of 14.2 in CFP suggesting a shared fold) as the best hits, supporting the conjecture that the PocR domain assumes a fold similar to the PAS and GAF domains. This observation is also consistent with the fact that some other commonly found ligand-binding domains in signaling proteins, namely the HNOBA domain of nitric oxide receptors and the CACHE domain seen in voltage-gated calcium channels and several bacterial methyl-accepting chemotactic receptors, also share a common fold with the PAS and GAF domains (Anantharaman and Aravind, 2000; Iyer et al., 2003; Reinelt et al., 2003). PocR domains contain three highly conserved cysteines (Fig. 3), which are situated on the first helical segment and the third strand of the conserved PAS-like core. When superimposed on to known structures of the PAS-like fold, the cysteines are predicted to point to the interior of the ligand-binding surface, and are likely to either serve as an attachment site for a prosthetic group (as seen in the GAF domains from phytochromes) or chelate a metal ion.
|
Biological functions of the MEDS and PocR domains and evidence for potential functional collaboration between them
Both the MEDS and PocR domains show certain contextual connections that might point to a functional relationship between the two, at least in certain systems. Proteins containing both these domains show lineage-specific expansions in the methanogenic archaeon Methanosarcina and often co-occur in the same polypeptide or predicted operons (Fig. 2). While the PocR domain is presently represented across a somewhat wider phyletic range than the MEDS domain (Fig. 1), both display analogous domain architectures. Furthermore, both domains might bind prosthetic groups or chlelate metals and recognize simple hydrocarbon derivatives such as 1,3-propanediol and dichloromethane.
A potential hint regarding the function of the MEDS domain is offered by its presence in genomes of both methane-utilizing methylotrophs and complex methanogens that can generate methane from a variety of substrates such as methylamines, methanol, formate and acetate. In contrast, the MEDS domain is absent in the simple methanogens that principally use CO2 as their substrate for methanogenesis. This suggests that the MEDS domain is used by the complex methanogens and methyltrophs to sense growth substrates in the form of methane derivatives and accordingly transmit signals via associated signaling domains to induce the necessary physiological changes. The versions of the MEDS domain found in the anti-sigma factors from actinobacteria are very distinct from those found in the methylotrophs and methanogens (Fig. 1). These proteins have been proposed to function as negative regulators of the actinomycete sigma factor SigB (Fig. 2), which is involved in the development of aerial mycelia and stress response (Cho et al., 2001; Roth et al., 2004). The presence of the MEDS domain in these anti-sigma factors suggests that they are regulated by a small-molecule ligand, whose presence or absence in the environment may act as a switch for the activity of their kinase domains.
In several distantly related bacteria, diverse regulators containing the PocR domain are found to be associated with operons for the catabolism or synthesis of 1,3-propanediol (Fig. 2). In Mther02000198 from Moorella thermoacetica, the PocR domain is found fused to a histidine kinase at the C-terminus and a vitamin B12 binding domain at the N-terminus (Fig. 2). Given that in most organisms the key enzyme involved in 1,3-propanediol metabolism, glycerol dehydratase, requires B12 as a cofactor (Bobik et al., 1992), it is not surprising that the functionality to sense both these substrates is combined in a single protein. However, in the complex methanogens, there is no association of the genes encoding PocR-containing proteins with any genes involved in propanediol metabolism. Instead, they are typically found associated with the genes encoding MEDS domain proteins suggesting a functional link between them. It is quite possible that the PocR domain in these organisms instead binds some of the larger methanogenic substrates such as acetate, which are not recognized by the MEDS domains and regulates the same or similar set of metabolic pathways as those regulated by the latter domain.
|
CONCLUSIONS |
|---|
|
TOPAbstractINTRODUCTIONSYSTEMS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
|---|
We characterize two novel domains in a variety of signaling proteins from methyltrophic and complex methanogenic microbes and present evidence that they might be involved in binding small hydrocarbon derivatives. These observations suggest a similar sensory mechanism utilized by methylotrophs and methanogens in sensing a related class of growth substrates. Additionally, both these domains appear to have been utilized in other prokaryotes as small molecule sensors in a range of other regulatory contexts. The study presented here may provide a new handle for understanding the sensory mechanisms used by organisms involved in the methane cycle. Furthermore, this study may also help in clarifying the diversity of regulatory mechanisms associated with the utilization and production of 1,3-propanediol, which might emerge as an important industrial raw material.
Received on February 23, 2005; revised on March 28, 2005; accepted on March 29, 2005
|
REFERENCES |
|---|
|
TOPAbstractINTRODUCTIONSYSTEMS AND METHODSRESULTS AND DISCUSSIONCONCLUSIONSREFERENCES |
|---|
Altschul, S.F., et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res., 25, 3389–3402
Anantharaman, V. and Aravind, L. (2000) Cache—a signaling domain common to animal Ca(2+)-channel subunits and a class of prokaryotic chemotaxis receptors. Trends Biochem. Sci., 25, 535–537[CrossRef][Web of Science][Medline].
Anantharaman, V. and Aravind, L. (2001) The CHASE domain: a predicted ligand-binding module in plant cytokinin receptors and other eukaryotic and bacterial receptors. Trends Biochem. Sci., 26, 579–582[CrossRef][Web of Science][Medline].
Anantharaman, V., et al. (2001) Regulatory potential, phyletic distribution and evolution of ancient, intracellular small-molecule-binding domains. J. Mol. Biol., 307, 1271–1292[CrossRef][Web of Science][Medline].
Aravind, L., et al. (2003) Evolutionary connections between bacterial and eukaryotic signaling systems: a genomic perspective. Curr. Opin. Microbiol., 6, 490–497[CrossRef][Web of Science][Medline].
Aravind, L. and Koonin, E.V. (1999) Gleaning non-trivial structural, functional and evolutionary information about proteins by iterative database searches. J. Mol. Biol., 287, 1023–1040[CrossRef][Web of Science][Medline].
Aravind, L. and Ponting, C.P. (1997) The GAF domain: an evolutionary link between diverse phototransducing proteins. Trends Biochem. Sci., 22, 458–459[CrossRef][Web of Science][Medline].
Bateman, A. (1997) The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem. Sci., 22, 12–13[Web of Science][Medline].
Bobik, T.A., et al. (1992) A single regulatory gene integrates control of vitamin B12 synthesis and propanediol degradation. J. Bacteriol., 174, 2253–2266
Cho, Y.H., et al. (2001) SigB, an RNA polymerase sigma factor required for osmoprotection and proper differentiation of Streptomyces coelicolor. Mol. Microbiol., 42, 205–214[CrossRef][Web of Science][Medline].
Cuff, J.A. and Barton, G.J. (2000) Application of multiple sequence alignment profiles to improve protein secondary structure prediction. Proteins, 40, 502–511[CrossRef][Web of Science][Medline].
Fischer, D. (2000) Hybrid fold recognition: combining sequence derived properties with evolutionary information. Pac. Symp. Biocomput., 119–130.
Iyer, L., et al. (2003) Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins. BMC Genomics, 4, 5[CrossRef][Medline].
Kayser, M.F., et al. (2002) Dichloromethane metabolism and C1 utilization genes in Methylobacterium strains. Microbiology, 148, 1915–1922
La Roche, S.D. and Leisinger, T. (1991) Identification of dcmR, the regulatory gene governing expression of dichloromethane dehalogenase in Methylobacterium sp. strain DM4. J. Bacteriol., 173, 6714–6721
Lo Conte, L., et al. (2002) SCOP database in 2002: refinements accommodate structural genomics. Nucleic Acids Res., 30, 264–267
Marchler-Bauer, A., et al. (2003) CDD: a curated Entrez database of conserved domain alignments. Nucleic Acids Res., 31, 383–387
Mougel, C. and Zhulin, I.B. (2001) CHASE: an extracellular sensing domain common to transmembrane receptors from prokaryotes, lower eukaryotes and plants. Trends Biochem. Sci., 26, 582–584[CrossRef][Web of Science][Medline].
Notredame, C., et al. (2000) T-Coffee: a novel method for fast and accurate multiple sequence alignment. J. Mol. Biol., 302, 205–217[CrossRef][Web of Science][Medline].
Pao, G.M. and Saier, M.H. (1995) Response regulators of bacterial signal transduction systems: selective domain shuffling during evolution. J. Mol. Evol., 40, 136–154[CrossRef][Web of Science][Medline].
Ponting, C.P. (1997) CBS domains in CIC chloride channels implicated in myotonia and nephrolithiasis (kidney stones). J. Mol. Med., 75, 160–163[Web of Science][Medline].
Ponting, C.P. and Aravind, L. (1997) PAS: a multifunctional domain family comes to light. Curr. Biol., 7, R674–R677[Web of Science][Medline].
Raynaud, C., et al. (2003) Molecular characterization of the 1,3-propanediol (1,3-PD) operon of Clostridium butyricum. Proc. Natl Acad. Sci. USA, 100, 5010–5015
Reinelt, S., et al. (2003) The structure of the periplasmic ligand-binding domain of the sensor kinase CitA reveals the first extracellular PAS domain. J. Biol. Chem., 278, 39189–39196
Rondon, M.R. and Escalante-Semerena, J.C. (1996) In vitro analysis of the interactions between the PocR regulatory protein and the promoter region of the cobalamin biosynthetic (cob) operon of Salmonella typhimurium LT2. J. Bacteriol., 178, 2196–2203
Rost, B. and Sander, C. (1993) Prediction of protein secondary structure at better than 70% accuracy. J. Mol. Biol., 232, 584–599[CrossRef][Web of Science][Medline].
Roth, V., et al. (2004) Differential and cross-transcriptional control of duplicated genes encoding alternative sigma factors in Streptomyces ambofaciens. J. Bacteriol., 186, 5355–5365
Tam, R. and Saier, M.H. (1993) Structural, functional, and evolutionary relationships among extracellular solute-binding receptors of bacteria. Microbiol. Rev., 57, 320–346
Taylor, B.L. and Zhulin, I.B. (1999) PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol. Mol. Biol. Rev., 63, 479–506
Taylor, B.L., et al. (1999) Aerotaxis and other energy-sensing behavior in bacteria. Annu. Rev. Microbiol., 53, 103–128[CrossRef][Web of Science][Medline].
Tyrrell, R., et al. (1997) The structure of the cofactor-binding fragment of the LysR family member, CysB: a familiar fold with a surprising subunit arrangement. Structure, 5, 1017–1032[Medline].
Vartak, N.B., et al. (1991) Sequence and evolution of the FruR protein of Salmonella typhimurium: a pleiotropic transcriptional regulatory protein possessing both activator and repressor functions which is homologous to the periplasmic ribose-binding protein. Res. Microbiol., 142, 951–963[Medline].
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Bateman Bioinformatics--The new home for protein sequence motifs Bioinformatics, January 1, 2006; 22(1): 2 - 2. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||