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Eukaryotic-Like Protein Kinases in the Prokaryotes and the Myxobacterial Kinome

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Eukaryotic-Like Protein Kinases in the Prokaryotes and the Myxobacterial Kinome Eukaryotic-like protein kinases in the prokaryotes and the myxobacterial kinome J. Pe´ rez†, A. Castan˜ eda-García†, H. Jenke-Kodama‡,R.Mu¨ ller§, and J. Mun˜ oz-Dorado†¶ †Departamento de Microbiologı´a,Instituto de Biotecnologı´a,Facultad de Ciencias, Universidad de Granada, Avda. Fuentenueva s/n, E-18071 Granada, Spain; ‡Department of Molecular Ecology, Institute of Biology, 10115 Berlin, Germany; and §Department of Pharmaceutical Biotechnology, Saarland University, D-66041 Saarbru¨cken, Germany Communicated by A. Dale Kaiser, Stanford University School of Medicine, Stanford, CA, July 18, 2008 (received for review March 13, 2008) Ser/Thr/Tyr kinases, which together comprise a major class of regu- mediated by a family of protein kinases exhibiting high sequence latory proteins in eukaryotes, were not believed to play an important similarities to their eukaryotic counterparts. The first eukaryotic- role in prokaryotes until recently. However, our analysis of 626 like protein kinase (ELK) reported in any prokaryote was found in prokaryotic genomes reveals that eukaryotic-like protein kinases the myxobacterium Myxococcus xanthus,a␦-Proteobacterium (6). (ELKs) are found in nearly two-thirds of the sequenced strains. We Publication of the M. xanthus DK1622 genome revealed that the have identified 2697 ELKs, most of which are encoded by multicellular strain contains a total of 99 ELKs (7), but this number is dwarfed strains of the phyla Proteobacteria (Myxococcales), Actinobacteria, by that of the myxobacterium Sorangium cellulosum So ce56 (8), Cyanobacteria, and Chloroflexi, and 2 Acidobacteria and 1 Plancto- which boasts 317, the largest numbers of ELKs reported so far mycetes. Astonishingly, 7 myxobacterial strains together encode 892 among the prokaryotes. ELKs, with 4 of the strains exhibiting a genomic ELK density similar to The M. xanthus genome also encodes a substantial number of that observed in eukaryotes. Most myxobacterial ELKs show a mod- typical bacterial 2-component systems (TCSs) (9). The need for a ular organization in which the kinase domain is located at the N complex regulatory system in this bacterium is evident from con- terminus. The C-terminal portion of the ELKs is highly diverse and sideration of its lifestyle. During growth, M. xanthus cells form often contains sequences with similarity to characterized domains, mobile, predatory communities known as ‘‘swarms,’’ which feed most of them involved in signaling mechanisms or in protein–protein cooperatively. Under starvation conditions, the cells initiate a interactions. However, many of these architectures are unique to the multicellular developmental program that culminates in the for- myxobacteria, an observation that suggests that this group exploits mation of macroscopic fruiting bodies filled with heat-resistant sophisticated and novel signal transduction systems. Phylogenetic myxospores. The spores remain dormant until nutrients are avail- reconstruction using the kinase domains revealed many orthologous able again, at which point they germinate, initiating a new vegeta- sequence pairs and a huge number of gene duplications that probably tive cycle (10, 11). Thus, the M. xanthus lifestyle requires the cells occurred after speciation. Furthermore, studies of the microsynteny in not only to monitor changes in the environment but also to commu- the ELK-encoding regions reveal only low levels of synteny among nicate with each other to coordinate movement and behavior. Myxococcus xanthus, Plesiocystis pacifica, and Sorangium cellulosum. Developmental sporulation also depends on the DKxanthene However, extensive similarities between M. xanthus, Stigmatella family of natural products (12). The other metabolites produced by aurantiaca, and 3 Anaeromyxobacter strains were observed, indicat- the cells (7) are assumed to provide it with a competitive advantage ing that they share regulatory pathways involving various ELKs. in the soil environment. Therefore, survival of M. xanthus also is intimately linked to the regulation of secondary metabolism. Anaeromyxobacter ͉ Myxococcus ͉ Plesiocystis ͉ Sorangium ͉ Stigmatella Growing evidence that ELKs play a role in development, virulence, metabolism, or stress adaptation in many other bac- terial genera (13, 14, 15, 16, 17) has prompted efforts to ignal transduction pathways in the eukaryotes typically are characterize the prokaryotic kinome (18, 19). However, the first mediated by protein kinases, which transfer the ␥-phosphate of S analysis in 2005 (18) was limited by the availability of only 125 ATP to a hydroxyl moiety (Ser, Thr, and/or Tyr) on a protein complete genome sequences, none of which belonged to the substrate. This kinase activity resides in a sequence of 250–300 myxobacteria, and the second analysis (19) focused on met- residues known as the catalytic domain, which consists of 12 agenomic sequences from a global ocean sampling and so was subdomains differentiated by their respective consensus motifs (1). unlikely to be representative of all prokaryotes. In this study, we The solved structure of a prototypical kinase domain (2) revealed aimed to assess whether typical kinases are widely represented that it consists of 2 lobes joined by a hinge segment. Catalysis occurs in the prokaryotes and to determine their exact number in each at the interface of the 2 lobes, where the catalytic residues interact prokaryotic genome. For this study we carried out a compre- with both ATP and the substrate. The key amino acids for the hensive bioinformatic analysis of the typical ELKs that constitute phosphotransfer reaction are the Lys of subdomain II and the Asp the kinome of the 7 myxobacterial strains sequenced. We also residues of subdomains VIb (D1) and VII (D2). Mutations in any surveyed the remaining 619 prokaryotic genomes deposited in of these residues are predicted to inactivate the proteins. the database of the National Center for Biotechnology Infor- For the kinases to function properly, their catalytic activity must mation (NCBI; http://www.ncbi.nlm.nih.gov/genomes/ be tightly controlled. Indeed, several different regulatory mecha- lproks.cgi) before January 15, 2008. This analysis revealed the nisms have been described (3). For example, 1 type of kinases presence of ELKs in approximately two-thirds of all prokaryotes. catalyzes an autophosphorylation reaction within the catalytic Comparison of the largest prokaryotic kinomes with those of domain, targeting a region termed the ‘‘activation segment’’ that runs from subdomain VII to VIII. Phosphorylation within this segment changes the conformation of the polypeptide and activates Author contributions: J.P. and J.M.-D. designed research; J.P. performed research; J.P., the enzyme (4). Proteins regulated by this mechanism require an A.C.-G., H.J.-K., R.M., and J.M.-D. analyzed data; and J.P., R.M., and J.M.-D. wrote the paper. Arg just upstream of Asp D1 and so are designated ‘‘RD kinases.’’ The authors declare no conflict of interest. Correspondingly, proteins that lack this Arg are known as ‘‘non-RD ¶To whom correspondence should be addressed. E-mail: [email protected]. kinases’’ (5). This article contains supporting information online at www.pnas.org/cgi/content/full/ Signal transduction pathways dependent on phosphorylation at 0806851105/DCSupplemental. Ser/Thr/Tyr also occur in the prokaryotes. This reaction also is © 2008 by The National Academy of Sciences of the USA 15950–15955 ͉ PNAS ͉ October 14, 2008 ͉ vol. 105 ͉ no. 41 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806851105 Downloaded by guest on September 28, 2021 several eukaryotes supports a link between ELKs and multicellularity. Results and Discussion ELKs in the Myxobacteria. The genomes of M. xanthus DK1622 (9.14 Mb containing 99 ELKs) and S. cellulosum So ce 56 (13.03 Mb containing 317 ELKs) encode the largest numbers of ELKs re- ported to date in the prokaryotes (7, 8). Five additional myxobac- terial genomes have become available recently, of which 2 are complete [Anaeromyxobacter sp. Fw109–5 (5.3 Mb) and Anaero- myxobacter dehalogenans 2CP-C (5.01 Mb)], and 3 are incomplete [Plesiocystis pacifica SIR-1 (10.59 Mb), Stigmatella aurantiaca DW4/ 3–1 (10.27 Mb), and Anaeromyxobacter sp. K (5 Mb)]. Consistent Fig. 1. Proportion of genome devoted to encoding ELKs in the myxobacteria as with the expectation of a high ELK content, we have found that a function of genome size. The equation of the exponential curve and the Anaeromyxobacter sp. K encodes 14 ELKs, A. dehalogenans en- coefficient of determination are indicated. codes 18, Anaeromyxobacter sp. Fw109–5 encodes 20, S. aurantiaca encodes 194, and P. pacifica encodes 230. Moreover, these numbers adaptability of the cells. Thus, evolution of these complex bacteria may increase when the incomplete genomes are completed. These may have selected cells with more ELKs in preference to using data confirm that the presence of a large number of genes encoding more TCSs. ELKs is a general feature of the myxobacteria. Together, the 7 myxobacteria encode at least 892 ELKs. Conservation of Catalytic and Regulatory Residues in the Myxobac- It presently is unclear why the myxobacterial kinome is so terial ELKs. Because kinase activity depends on the presence of 3 extensive. However, the level of regulation required to control their active site residues, we have analyzed all myxobacterial ELKs for the complex social lifestyles provides an attractive explanation. Four presence of these amino acids. This analysis revealed that the 3 cell types have been identified in
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