Weiru Wang and Sung Hou

Department of Chemistry and Lawrence Berkeley National Laboratory, University of California, Berkeley, California

While the chemotactic signaling pathway of bacteria has been established [1,2] well enough to enable accurate computer simulation of the migration of virtual bacteria [3], detailed molecular mechanisms underlying ligand-mediated transmembrane signaling, high receptor sensitivity, receptor adaptation, and one broad dynamic range of sensitivity to attractants remain to be elucidated.

Bacteria rapidly respond to changes in concentrations of critical chemicals in their environment by chemotaxis—that is, a swimming pattern biased toward or away from particular stimuli [4]. The chemotaxis pathway includes chemosensory receptors and a phosphotransfer system known as the two-component signal transduction pathway [5-8]. It is well established that bacteria sense their environmental changes over time [9]. Like many other sensory perception processes, bacterial chemotaxis has high sensitivity and broad dynamic range [10-12]. The sensitivity allows the binding of attractants to less than 1% of the receptors to induce increased swimming motion of Escherichia coli [13]; this high sensitivity does not appear to be due to a signal amplification step downstream of the receptor [14]. As for the dynamic range, bacteria can detect the gradient of attractants such as aspartate under background concentrations (from nanomolar to millimolar) spanning five to six orders of magnitude [13,15,16].

Most bacterial chemoreceptors belong to a family of transmembrane methyl-accepting chemotaxis proteins (MCPs). MCps can be divided into at least four subfamilies on the basis of the disposition of hydrophobic regions that are predicted to be transmembrane helices by hydrophathy analysis

[17]. Family A includes two transmembrane helices separated by a substantial periplasmic domain (Fig. 1). Whereas the other families possess less periplasmic and less transmembrane components (for a recent review, see Falke and Kim

[18]). Family A also includes the chemoreceptors for aspartate, serine, ribose and galactose, peptide, citrate, and osmolarity [19,20]. The architectures of selected family chemorecep-tors are well understood and are likely to represent many other members of family A. The folding unit of the chemore-ceptor is a stable homodimer [21]. Each receptor monomer consists of a ligand binding region (periplasmic sensory domain) made up by an anti-parallel, four-helix bundle (a1, a2, a3, and a4), an antiparallel two-helix (TM1, TM2) transmembrane region, and a long two-helix hairpin region (cyto-plasmic signaling domain) (Fig. 1). The receptor dimer is thus an elongated helical bundle thought to be oriented normal to the membrane plane [22-27]. The length of one E. coli serine receptor model spans « 380 A from one end to the other [27]. The incoming signal propagates through the cytoplasmic domain, which is coupled by a scaffolding protein CheW to the signaling kinase CheA [8,28]. CheA in turn regulates two response regulators: CheY (in the phosphosignaling branch of the pathway) and CheB (in the adaptation branch). Attractant binding attenuates CheA activity and, ultimately, via the phosphosignaling branch, reduces the overall frequency of tumbling (by clockwise rotation of flagella) (Fig. 2) [8].

Figure 1 A model of intact E. coli Tsr chemotaxis receptor dimer [27]: one monomer is blue, the other pink. The presumed membrane bilayer is represented by a gray horizontal band. The model is about 380 A long and consists of about 80-A-long ligand binding domains, an about 40-A long transmembrane domain, and an about 260-A long cytoplasmic domain. The length of each domain is shown. (Left) Ribbon diagram of the intact Tsr dimer model viewed perpendicular to the non-crystallographic two-fold symmetry axis. The dimensions are scaled to match those of the schematic figure at right. One monomer is purple, the other cyan. Methylation sites are marked by yellow balls in one monomer and orange balls in the other, and the ligand serine is red (partially hidden at upper left corner). Some landmark residues are shown.

Figure 1 A model of intact E. coli Tsr chemotaxis receptor dimer [27]: one monomer is blue, the other pink. The presumed membrane bilayer is represented by a gray horizontal band. The model is about 380 A long and consists of about 80-A-long ligand binding domains, an about 40-A long transmembrane domain, and an about 260-A long cytoplasmic domain. The length of each domain is shown. (Left) Ribbon diagram of the intact Tsr dimer model viewed perpendicular to the non-crystallographic two-fold symmetry axis. The dimensions are scaled to match those of the schematic figure at right. One monomer is purple, the other cyan. Methylation sites are marked by yellow balls in one monomer and orange balls in the other, and the ligand serine is red (partially hidden at upper left corner). Some landmark residues are shown.

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