Systems biology of bacterial chemotaxis Melinda D Baker 1, Peter M Wolanin 2 and Jeffry B Stock 1

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1 Systems biology of bacterial chemotaxis Melinda D Baker 1, Peter M Wolanin 2 and Jeffry B Stock 1 Motile bacteria regulate chemotaxis through a highly conserved chemosensory signal-transduction system. System-wide analyses and mathematical modeling are facilitated by extensive experimental observations regarding bacterial chemotaxis proteins, including biochemical parameters, protein structures and protein protein interaction maps. Thousands of signaling and regulatory chemotaxis proteins within a bacteria cell form a highly interconnected network through distinct protein protein interactions. A bacterial cell is able to respond to multiple stimuli through a collection of chemoreceptors with different sensory modalities, which interact to affect the cooperativity and sensitivity of the chemotaxis response. The robustness or insensitivity of the chemotaxis system to perturbations in biochemical parameters is a product of the system s hierarchical network architecture. Addresses 1 Princeton University, Department of Molecular Biology, Lewis Thomas Laboratory, Princeton, NJ 08544, USA 2 Signum Biosciences, Inc., Monmouth Junction, NJ, USA Corresponding author: Stock, Jeffry B (jstock@princeton.edu) This review comes from a themed issue on Cell regulation Edited by Werner Goebel and Stephen Lory Available online 9th March /$ see front matter # 2005 Elsevier Ltd. All rights reserved. DOI /j.mib Introduction The bacterial chemotaxis system provides a paradigm for understanding the principles of information processing and decision making that control processes ranging from motility and cytoskeleton dynamics to growth and gene expression. The seminal work, initiated by Julius Adler and his colleagues almost 50 years ago, established that Escherichia coli chemotaxis is mediated by a discrete set of interacting genes and proteins that operate as a functional unit distinct from systems that mediate cell growth and metabolism [1]. The chemotaxis system provides one of the clearest examples of the hierarchical organization of cellular networks into systemic modules serving different functional requisites [2]. High-resolution mapping of the network of protein protein interactions that constitute the chemotaxis system has provided a basis for understanding how network architectures evolve to generate robust functional outputs [3]. Bacterial chemotaxis systems The E. coli chemotaxis system (Figure 1) is encoded by six essential che genes: chea, cheb, cher, chew, chey and chez; and five partially redundant chemoreceptor genes, tsr, tar, trg, tap, and aer [4 6]. The products of these genes form a highly interconnected network of interacting proteins, all of which appear to function solely within the context of the chemotaxis system. In the cell s sensory regulation these five chemoreceptors serve only in the control of cell motility. Many studies of bacterial chemotaxis focus on the network of interacting chemotaxis genes, but the chemotaxis genetic system and the chemotaxis protein network are very different entities. The genetic operons that encode the chemotaxis system are subsumed within the flagellar regulon that encodes and regulates the expression of the flagellar motility apparatus [7]. In the flagellar system the regulation of gene expression and protein function are intimately associated [8], whereas the chemotaxis signaltransduction network appears to be completely bereft of any genetic regulatory element [9]. In contrast to what might be presumed from the genetics of the chemotaxis and motility systems, they are as different in structure and function as brain and muscle are. E. coli swim by rotating long helical flagellar filaments that are attached to rotary motors embedded in the cell envelope [10]. There are typically six or seven independently functioning motors distributed over the cell surface, each of which switches between clockwise and counterclockwise rotation. The chemotaxis system functions to convert sensory information into an analog signal that controls the probability of motor switching. The CheA protein is a histidine protein-kinase (HPK) that catalyzes the transfer of phosphoryl groups from ATP to one of its own histidine imidazole side-chains [9]. The phosphoryl group is subsequently transferred from CheA to an aspartyl side-chain in the CheY protein. Phosphorylated CheY (CheYP) readily dissociates from CheA and freely diffuses to the flagellar motor switch, where it binds and acts as an allosteric regulator in shifting the clockwise-counterclockwise equilibrium towards clockwise rotation [11 13]. Non-phosphorylated CheY does not appear to bind to the flagellar motor [11,14]. Dephosphorylation of CheYP is mediated by the phosphatase CheZ [15,16 ]. The analog signal generated by the chemotaxis system is the cytoplasmic concentration of CheYP. The principle mechanism by which CheYP levels are modulated to generate chemotactic responses is through chemoreceptor-mediated control of CheA autokinase activity.

2 188 Cell regulation Figure 1 Protein protein interaction map for the E. coli chemotaxis system. Solid lines connecting proteins, or single domains within multidomain proteins, depict direct protein protein interactions. Homologous protein domains are colored similarly: green represents the SH3-like CheW domain; cyan represents the CheY response-regulator domain; and orange-brown represents a coiled-coil domain that forms a four-helix bundle upon dimerization. Unshaded domains do not possess homologs within the chemotaxis system. The CheR and the esterase domain of CheB are both outlined in purple because they both participate in covalent modification of the chemoreceptors. P1, P2 and P4 of CheA are all outlined in blue because together they provide crucial residues for ATP binding and phosphotransfer. Abbreviations: CC, coiled-coil domain; P1, histidine phosphotransfer domain; P2, response regulator binding domain; P3, dimerization domain; P4, ATP binding domain; P5, regulator domain; Y B, CheY response regulator domain of CheB. The chemotaxis proteins encoded by the che genes are composed of several structurally distinct protein domains (Figure 1). CheW, CheY and CheZ are all single-domain proteins, the domain structures of which are also present in other essential Che proteins [17]. CheB has two domains, one of which is a response-regulator domain homologous to CheY. The CheA polypeptide chain folds into five domains, designated P1 P5 [18]. P1, P2 and P4 provide essential functions, including ATP-binding and phosphorylation, that are unique among chemotaxis proteins. P3 is a dimeric coiled-coil domain related to the cytoplasmic domain of the chemoreceptors and CheZ [15,18]. P5 is homologous to CheW [18]. The chemoreceptors, Tsr, Tar, Tap, Trg and Aer, each contain a highly variable membrane-associated sensory domain linked to a common cytoplasmic C-terminal coiled-coil domain [5,19]. CheA, CheW and chemoreceptor subunits associate to form large multimeric complexes [20,21 ]. An E. coli cell typically has over ten thousand receptor subunits clustered together with a comparable number of CheW and CheA subunits [22 ]. Other chemotaxis proteins interact with this core receptor CheW CheA assembly [23 25]. In systems of interacting proteins, such as ribosomes, many different types of subunits come together, like pieces in a jigsaw puzzle, to form a structural entity with precise composition and defined architecture. By contrast, the network of protein protein interactions within the chemotaxis system constitutes a small-world network with ill-defined boundaries, held together by a multiplicity of dynamic associations [26]. The five different chemoreceptor subtypes appear to be intermingled each contributing hundreds, or in the case of the more abundant subtypes, thousands, of subunits to a cluster [27 ]. Essentially, the sensory domains of these subunits function as antennae in order to funnel information into the network of interacting coiled-coils on the opposite side of the cytoplasmic membrane. Each receptor subtype detects its own characteristic spectrum of stimuli. Input signals perturb the frequencies and amplitudes of sensory domain movements on a millisecond time-scale. These inputs affect the highly connected array of coiled-coil chemoreceptor domains to cause changes in the frequency of CheY phosphorylation, on a time-scale of tenths of seconds [14]. Changes in CheYP, in turn, cause changes in the frequency of flagella motor switching, on a time-scale of seconds. Sensory domain inputs also cause changes in methylation of glutamate residues within the coiled-coil receptor domains [4,5]. These changes occur over longer timescales in order to adjust the quantitative relationship between a given sensory input and its associated output, a process that has been termed adaptation; CheR and CheB mediate these covalent receptor modifications [17]. CheR is a methyltransferase that catalyzes the methylesterification of specific glutamate residues in receptor coiled-coil domains, and the CheB C-terminal domain is an esterase that removes these methyl groups. Each individual in a population of bacteria exhibits its own characteristic flagella switching frequency. This variability is often not addressed in discussions of perfect adaptation of the chemotaxis system [3,28,29,30 ]. Even in a constant environment, the behavior of an individual fluctuates too much over time to indicate a perfectly adapted state. However, the average behavior within a population adapts more-or-less perfectly to a chemotaxis signal [31 ]. A given E. coli cell generally only has one or two receptor clusters located at one or both poles [20]. It seems likely that immediately after division, each daughter cell inherits one cluster at the old pre-division pole. As cells grow and prepare to divide, a second cluster at the opposing pole is generated so that after division one daughter gets the old cluster and the other gets the new cluster. There is evidence suggesting that the receptors in old clusters do not interchange with receptors in new clusters [27,32]. Since methylation-associated covalent modifications of receptors can be essentially irreversible, one would expect functional differences between

3 Systems biology of bacterial chemotaxis Baker, Wolanin and Stock 189 old and new clusters. Thus, ageing could contribute to non-genetic individuality of bacterial behavior [33]. Figure 2 Beyond E. coli E. coli has a rather abbreviated chemotaxis system; other motile bacteria often have considerably more complex arrangements of the basic components that are found in E. coli [6,34]. There are even significant variations between E. coli and other enteric bacteria, such as Salmonella. Although all of the Salmonella and E. coli components are functionally interchangeable, Salmonella has an additional component, CheV, that is composed of a CheY domain linked to a CheW domain [34]. This additional component might provide a methylation-independent adaptation mechanism to Salmonella chemotaxis, a mechanism that appears to be lacking in E. coli [35]. In addition to this difference between Che components, Salmonella and E. coli exhibit significant differences in their sensory modalities [4]. In E. coli, for instance, the maltose transport system is linked to Tar, whereas in Salmonella this link is missing. There is considerably greater divergence in more distantly related species [6,34]. There is no clear relationship between either the structures or the sensory specificities of the variable membrane-associated domains of the chemotaxis receptors in enteric bacteria and the corresponding protein components in other species. The core Che components the chemoreceptor coiled-coil domains, CheA, CheW, and CheY of the essential E. coli system are highly conserved throughout all bacterial chemotaxis systems. Nonetheless, in other species there tend to be more variants of each domain and a variety of new combinations of linked domains such as occurs in CheV. In many species, it is apparent that two or more chemotaxis systems, each with their own complement of Che components, interact [36]. Although the expression and function of these systems might be somewhat orthogonal, they frequently function as an integrated unit. The potential added complexity of this type of systemic redundancy is enormous. Crosstalk between chemotaxis systems and other functional modules Sensory input and effector output functions for chemotaxis are generally supplied by distinct, independently functioning systemic modules (Figure 2). Early studies showed that systems that mediate the uptake of nutrients, such as glucose and galactose, also serve as sensors for chemotaxis [37]. The systemic connections outlined in Figure 2 are mediated generally by direct protein protein contacts. Less well-defined are the numerous connections that are mediated by small molecules; changes in ATP or in the methyl-donor S-adenosylmethionine lead to changes in chemotaxis behavior. It is possible that these metabolites function as second-messenger indicators of the cell s metabolic status signals for hunger or satiety The E. coli chemotaxis system receives inputs from and delivers outputs to modular cellular systems that function independently of chemotaxis. The ribose, glucose, peptide, maltose and galactose systems function in the uptake and utilization of nutrients and in the regulation of expression of genes within the system. These systems provide sensory inputs to the E. coli chemotaxis system through specific protein protein interactions. Similarly, the chemotaxis system, which functions in the processing of sensory information, serves as an input for the motility system. [4]. Similar considerations apply concerning the effects of various other intracellular constituents including ph, ionic composition and membrane potential. Differentiating individual system behaviors from population averages and determining synergies that emerge from networks of interacting systems is crucial to understanding the function of system-network architectures. This is amply illustrated by the evolution of our understanding of the chemotaxis systems of individual cells. It was originally supposed that the chemotaxis responses of a given cell could be understood as the sum of the activities of thousands of independent receptors, each controlling an associated histidine kinase, and each making an independent contribution to the pool of CheYP; this is a summation of multiple examples of the system outlined in Figure 1. Individual receptor types within receptor-signaling complexes, in which numerous different receptor dimers intermingle, show altered sensitivities compared with those of homogeneous receptor populations [38 ]. Just as connections between subcellular systems allow for the integration of functions within individual cells, links between individuals retain these functions for the overall benefit of a population. The overarching significance of

4 190 Cell regulation intercellular communication, or quorum sensing, to bacterial physiology has only recently begun to be appreciated [39,40]. Bacterial chemotaxis provides a particularly useful paradigm for understanding the interplay between individuals within populations. Just as it was generally assumed that receptors function independently, it was assumed that the chemotaxis of bacterial populations could be understood as the sum of the behaviors of each individual cell. Recent findings indicate, however, that social interactions are the overriding determinants of chemotaxis behavior [41,42]. The specificities of bacterial sensory systems are attuned to small molecule metabolites that are secreted by other cells. These often function as attractants so that, as a result, individuals tend to congregate together, leading to the formation of cooperative clusters of cells with novel emergent properties, such as bioluminescence. Robustness and the evolution of network architectures Sensory regulation systems generally adapt to background stimuli. A familiar example of this is human vision: once our eyes have adapted to the dark, we can detect relatively low levels of photons and more intense light is blinding, until our eyes have adjusted to the new conditions. Adaptive sensory systems approximately follow the Weber-Fechner Law: the smallest change in stimulus intensity that can be sensed (DS) generally increases with the background stimulus intensity (S) so that DS/S remains roughly constant [43]. The sensitivity of the bacterial chemotaxis system exhibits similar adaptations [44]. Chemotaxis adaptation depends, largely, on stimulus-induced changes in chemoreceptor methylation that act to maintain the system in a constant state, over a wide range of background-stimulus intensities (Figure 3). When chemoreceptors are activated to generate CheYP they are more likely to be demethylated, and demethylated chemoreceptors become inactive. Conversely, when chemoreceptors are inactive they are more likely to be methylated, which favors activation. This simple integral feedback mechanism is relatively insensitive to any specific parameters of the system, such as absolute rates of methylation and demethylation, numbers or types of chemoreceptors, and relationships between methylation and phosphorylation [3,28,29,30 ]; it is, in a word, robust. One of the primary objectives of systems biology is to formulate biological laws that are akin to the laws of physics. The principle of robust adaptation is potentially such a biological law. It has been proposed that the robust adaptation mechanism of the chemotaxis system was the crucial step that allowed its subsequent evolution [3]. This proposition is supported by the fact that, whereas numerous microbial and plant signaling systems use signaling pathways that involve HPKs and response regulators that are homologous to CheA and CheY, bacterial chemotaxis systems appear to be unique in their Figure 3 Schematic of two-state chemoreceptor signaling in E. coli chemotaxis. Many computational models of bacterial chemotaxis invoke a two-state formalism as depicted above. Receptor-signaling complexes (RSCs) adopt a kinase-inactive counterclockwise (CCW) promoting or kinase-active clockwise (CW) promoting state. When the complexes are in a steady state, the rates of methylation and demethylation must be equal, such that the ratio of CW to CCW receptor-signaling complexes is returned to a constant value. The are three key mechanistic features of the system: attractant stimuli have a greater affinity for inactive receptors whereas repellant stimuli favor active receptors; CheB acts only on active receptors independent of receptor concentration; and CheR works at saturation of its substrate. A feedback mechanism exists in which phosphorylation of CheB by active receptor-signaling complexes increases the demethylating activity of CheB towards active receptor-signaling complexes. utilization of chemoreceptor methylation and demethylation to effect adaptive responses [9]. Can the robustness hypothesis be applied as a general principle that underlies the evolution of biological systems? It seems likely that there is an underlying robustness in biological systems that enables mutational variations to occur, without overly compromising the activity of the system, and this enables the system to evolve [2]. In fact, other robust principles might be gleaned from an examination of the bacterial chemotaxis mechanism. The CheA CheY phospho-relay mechanism is used for a wide range of different signal transduction systems [9]. The underlying kinetically controlled switching mechanism appears to provide a robust strategy for linking a sensory input to an output response. Measurements of the kinetics of the phosphotransfer and methyltransfer reactions, as well as protein protein interaction dynamics, have provided sufficient information to enable computer simulations of bacterial chemotaxis. These have generally been based on a two-state formalism [3,29,30,45]. A cooperative two-state switch-like mechanism appears to be essential for signaling as well as adaptation. Two-state behaviors have generally been associated with crucial regulatory proteins [46]. Perhaps this stems from the robustness of the two-state principle of systemic organization.

5 Systems biology of bacterial chemotaxis Baker, Wolanin and Stock 191 Conclusions The classification of proteins on the basis of their encoded amino acid sequence similarities has resulted in the formulation of families and superfamilies of proteins. The value of this approach has been amply established by its utility in predicting structural and functional relationships. The presence of a particular set of interacting proteins, however, cannot always be predicted on the basis of traditional phylogenetic classifications. Microbial species have a propensity for horizontal gene transfer that tends to obscure species boundaries and promote the evolution of organized, functionally coordinated modules of interacting components. Through an analysis of the chemotaxis system, it can be seen how such protein protein interaction networks might evolve, on the basis of a few robust principles. These design principles enable cooperative adjustment of the component activities to provide the exquisitely specific structures and functions that characterize any living system as a whole. Acknowledgements Research in our laboratory is supported by grant GM from the National Institutes of Health awarded to JBS, and a Science Research Dissertation Fellowship provided by the United Negro College Fund- Merck Science Initiative and Merck Research Laboratories awarded to MDB. We thank NS Wingreen for helpful discussions and communications of unpublished work cited in this review. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Adler J: Chemoreceptors in bacteria. Science 1969, 166: Hartwell LH, Hopfield JJ, Leibler S, Murray AW: From molecular to modular cell biology. Nature 1999, 402:C47-C Barkai N, Leibler S: Robustness in simple biochemical networks. 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