Framework for exploring the sensory repertoire of the human gut microbiota.

Bacteria sense changes in their environment and transduce signals to adjust their cellular functions accordingly. For this purpose, bacteria employ various sensors feeding into multiple signal transduction pathways. Signal recognition by bacterial sensors is studied mainly in a few model organisms, but advances in genome sequencing and analysis offer new ways of exploring the sensory repertoire of many understudied organisms. The human gut is a natural target of this line of study: it is a nutrient-rich and dynamic environment and is home to thousands of bacterial species whose activities impact human health. Many gut commensals are also poorly studied compared to model organisms and are mainly known through their genome sequences. To begin exploring the signals human gut commensals sense and respond to, we have designed a framework that enables the identification of sensory domains, prediction of signals that they recognize, and experimental verification of these predictions. We validate this framework's functionality by systematically identifying amino acid sensors in selected bacterial genomes and metagenomes, characterizing their amino acid binding properties, and demonstrating their signal transduction potential.IMPORTANCESignal transduction is a central process governing how bacteria sense and respond to their environment. The human gut is a complex environment with many living organisms and fluctuating streams of nutrients. One gut inhabitant, Escherichia coli, is a model organism for studying signal transduction. However, E. coli is not representative of most gut microbes, and signaling pathways in the thousands of other organisms comprising the human gut microbiota remain poorly understood. This work provides a foundation for how to explore signals recognized by these organisms.

Bacterial sensor evolved by decreasing complexity.

Bacterial receptors feed into multiple signal transduction pathways that regulate a variety of cellular processes including gene expression, second messenger levels and motility. Receptors are typically activated by signal binding to ligand binding domains (LBD). Cache domains are omnipresent LBDs found in bacteria, archaea, and eukaryotes, including humans. They form the predominant family of extracytosolic bacterial LBDs and were identified in all major receptor types. Cache domains are composed of either a single (sCache) or a double (dCache) structural module. The functional relevance of bimodular LBDs remains poorly understood. Here, we identify the PacF chemoreceptor in the phytopathogen Pectobacterium atrosepticum that recognizes formate at the membrane distal module of its dCache domain, triggering chemoattraction. We further demonstrate that a family of formate-specific sCache domains has evolved from a dCache domain, exemplified by PacF, by losing the membrane proximal module. By solving high-resolution structures of two family members in complex with formate, we show that the molecular basis for formate binding at sCache and dCache domains is highly similar, despite their low sequence identity. The apparent loss of the membrane proximal module may be related to the observation that dCache domains bind ligands typically at the membrane distal module, whereas the membrane proximal module is not involved in signal sensing. This work advances our understanding of signal sensing in bacterial receptors and suggests that evolution by reducing complexity may be a common trend shaping their diversity. Significance: Many bacterial receptors contain multi-modular sensing domains indicative of complex sensory processes. The presence of more than one sensing module likely permits the integration of multiple signals, although, the molecular detail and functional relevance for these complex sensors remain poorly understood. Bimodular sensory domains are likely to have arisen from the fusion or duplication of monomodular domains. Evolution by increasing complexity is generally believed to be a dominant force. Here we reveal the opposite - how a monomodular sensing domain has evolved from a bimodular one. Our findings will thus motivate research to establish whether evolution by decreasing complexity is typical of other sensory domains.

FlhE functions as a chaperone to prevent formation of periplasmic flagella in Gram-negative bacteria.

The bacterial flagellum is an organelle utilized by many Gram-negative bacteria to facilitate motility. The flagellum is composed of a several µm long, extracellular filament that is connected to a cytoplasmic rotor-stator complex via a periplasmic rod. Composed of ∼20 structural proteins, ranging from a few subunits to several thousand building blocks, the flagellum is a paradigm of a complex macromolecular structure that utilizes a highly regulated assembly process. This process is governed by multiple checkpoints that ensure an ordered gene expression pattern coupled to the assembly of the various flagellar building blocks in order to produce a functional flagellum. Using epifluorescence, super-resolution STED and transmission electron microscopy, we discovered that in Salmonella , the absence of one periplasmic protein, FlhE, prevents proper flagellar morphogenesis and results in the formation of periplasmic flagella. The periplasmic flagella disrupt cell wall synthesis, leading to a loss of the standard cell morphology resulting in cell lysis. We propose a model where FlhE functions as a periplasmic chaperone to control assembly of the periplasmic rod to prevent formation of periplasmic flagella. Our results highlight that bacteria evolved sophisticated regulatory mechanisms to control proper flagellar assembly and minor deviations from this highly regulated process can cause dramatic physiological consequences.

MiST 4.0: a new release of the microbial signal transduction database, now with a metagenomic component.

Signal transduction systems in bacteria and archaea link environmental stimuli to specific adaptive cellular responses. They control gene expression, motility, biofilm formation, development and other processes that are vital to survival. The microbial signal transduction (MiST) database is an online resource that stores tens of thousands of genomes and allows users to explore their signal transduction profiles, analyze genomes in bulk using the database application programming interface (API) and make testable hypotheses about the functions of newly identified signaling systems. However, signal transduction in metagenomes remained completely unexplored. To lay the foundation for research in metagenomic signal transduction, we have prepared a new release of the MiST database, MiST 4.0, which features over 10 000 metagenome-assembled genomes (MAGs), a scaled representation of proteins and detailed BioSample information. In addition, several thousands of new genomes have been processed and stored in the database. A new interface has been developed that allows users to seamlessly switch between genomes and MAGs. MiST 4.0 is freely available at https://mistdb.com; metagenomes and MAGs can also be explored using the API available on the same page.

Diverse domain architectures of CheA histidine kinase, a central component of bacterial and archaeal chemosensory systems.

IMPORTANCE: We found that in contrast to the best-studied model organisms, such as Escherichia coli and Bacillus subtilis, most bacterial and archaeal species have a CheA protein with a different domain composition. We report variations in CheA architecture, such as domain duplication and acquisition as well as class-specific domain composition. Our results will be of interest to those working on signal transduction in bacteria and archaea and lay the foundation for experimental studies.

Attractant and repellent induce opposing changes in the four-helix bundle ligand-binding domain of a bacterial chemoreceptor.

Motile bacteria navigate toward favorable conditions and away from unfavorable environments using chemotaxis. Mechanisms of sensing attractants are well understood; however, molecular aspects of how bacteria sense repellents have not been established. Here, we identified malate as a repellent recognized by the MCP2201 chemoreceptor in a bacterium Comamonas testosteroni and showed that it binds to the same site as an attractant citrate. Binding determinants for a repellent and an attractant had only minor differences, and a single amino acid substitution in the binding site inverted the response to malate from a repellent to an attractant. We found that malate and citrate affect the oligomerization state of the ligand-binding domain in opposing way. We also observed opposing effects of repellent and attractant binding on the orientation of an alpha helix connecting the sensory domain to the transmembrane helix. We propose a model to illustrate how positive and negative signals might be generated.

Ubiquitous purine sensor modulates diverse signal transduction pathways in bacteria.

Purines and their derivatives are key molecules for controlling intracellular energy homeostasis and nucleotide synthesis. In eukaryotes, including humans, purines also act as signaling molecules that mediate extracellular communication and control key cellular processes, such as proliferation, migration, differentiation, and apoptosis. However, the signaling role of purines in bacteria is largely unknown. Here, by combining structural and sequence information, we define a purine-binding motif, which is present in sensor domains of thousands of bacterial receptors that modulate motility, gene expression, metabolism and second messenger turnover. The screening of compound libraries and microcalorimetric titrations of selected sensor domains validated their ability to specifically bind purine derivatives. The physiological relevance of purine sensing was demonstrated in a second messenger signaling system that modulates c-di-GMP levels.

Diverse domain architectures of CheA histidine kinase, a central component of bacterial and archaeal chemosensory systems.

Chemosensory systems in bacteria and archaea are complex, multi-protein pathways that enable rapid cellular responses to environmental changes. The CheA histidine kinase is a central component of chemosensory systems. In contrast to other histidine kinases, it lacks a sensor (input) domain and utilizes dedicated chemoreceptors for sensing. CheA is a multi-domain protein; in model organisms as diverse as Escherichia coli and Bacillus subtilis, it contains five single-copy domains. Deviations from this canonical domain architecture have been reported, however, a broad genome-wide analysis of CheA diversity is lacking. Here, we present results of a genomic survey of CheA domain composition carried out using an unbiased set of thousands of CheA sequences from bacteria and archaea. We found that four out of five canonical CheA domains comprise a minimal functional unit (core domains), as they are present in all surveyed CheA homologs. The most common deviations from a classical five-domain CheA architecture are the lack of a P2/CheY-binding domain, which is missing from more than a half of CheA homologs and the acquisition of a response regulator receiver (CheY-like) domain, which is present in ~35% of CheA homologs. We also document other deviations from classical CheA architecture, including bipartite CheA proteins, domain duplications and fusions, and reveal that phylogenetically defined CheA classes have pre-dominant domain architectures. This study lays a foundation for a better classification of CheA homologs and identifies targets for experimental investigations.

Amine-recognizing domain in diverse receptors from bacteria and archaea evolved from the universal amino acid sensor.

Bacteria possess various receptors that sense different signals and transmit information to enable an optimal adaptation to the environment. A major limitation in microbiology is the lack of information on the signal molecules that activate receptors. Signals recognized by sensor domains are poorly reflected in overall sequence identity, and therefore, the identification of signals from the amino acid sequence of the sensor alone presents a challenge. Biogenic amines are of great physiological importance for microorganisms and humans. They serve as substrates for aerobic and anaerobic growth and play a role of neurotransmitters and osmoprotectants. Here, we report the identification of a sequence motif that is specific for amine-sensing sensor domains that belong to the Cache superfamily of the most abundant extracellular sensors in prokaryotes. We identified approximately 13,000 sensor histidine kinases, chemoreceptors, receptors involved in second messenger homeostasis and Ser/Thr phosphatases from 8,000 bacterial and archaeal species that contain the amine-recognizing motif. The screening of compound libraries and microcalorimetric titrations of selected sensor domains confirmed their ability to specifically bind biogenic amines. Mutants in the amine-binding motif or domains that contain a single mismatch in the binding motif had either no or a largely reduced affinity for amines. We demonstrate that the amine-recognizing domain originated from the universal amino acid-sensing Cache domain, thus providing insight into receptor evolution. Our approach enables precise "wet"-lab experiments to define the function of regulatory systems and therefore holds a strong promise to enable the identification of signals stimulating numerous receptors.

Evolutionary history of MEK1 illuminates the nature of deleterious mutations.

Mutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the human MAP2K1 gene, is one of the central components of the MAPK pathway and more than a hundred somatic mutations in the MAP2K1 gene were identified in various tumors. Germline mutations deregulating MEK1 also lead to congenital abnormalities, such as the cardiofaciocutaneous syndrome and arteriovenous malformation. Evaluating variants associated with a disease is a challenge, and computational genomic approaches aid in this process. Establishing evolutionary history of a gene improves computational prediction of disease-causing mutations; however, the evolutionary history of MEK1 is not well understood. Here, by revealing a precise evolutionary history of MEK1, we construct a well-defined dataset of MEK1 metazoan orthologs, which provides sufficient depth to distinguish between conserved and variable amino acid positions. We matched known and predicted disease-causing and benign mutations to evolutionary changes observed in corresponding amino acid positions and found that all known and many suspected disease-causing mutations are evolutionarily intolerable. We selected several variants that cannot be unambiguously assessed by automated prediction tools but that are confidently identified as "damaging" by our approach, for experimental validation in Drosophila. In all cases, evolutionary intolerant variants caused increased mortality and severe defects in fruit fly embryos confirming their damaging nature. We anticipate that our analysis will serve as a blueprint to help evaluate known and novel missense variants in MEK1 and that our approach will contribute to improving automated tools for disease-associated variant interpretation.

Two disulfide-reducing pathways are required for the maturation of plastid c-type cytochromes in Chlamydomonas reinhardtii.

In plastids, conversion of light energy into ATP relies on cytochrome f, a key electron carrier with a heme covalently attached to a CXXCH motif. Covalent heme attachment requires reduction of the disulfide-bonded CXXCH by CCS5 and CCS4. CCS5 receives electrons from the oxidoreductase CCDA, while CCS4 is a protein of unknown function. In Chlamydomonas reinhardtii, loss of CCS4 or CCS5 yields a partial cytochrome f assembly defect. Here, we report that the ccs4ccs5 double mutant displays a synthetic photosynthetic defect characterized by a complete loss of holocytochrome f assembly. This defect is chemically corrected by reducing agents, confirming the placement of CCS4 and CCS5 in a reducing pathway. CCS4-like proteins occur in the green lineage, and we show that HCF153, a distant ortholog from Arabidopsis thaliana, can substitute for Chlamydomonas CCS4. Dominant suppressor mutations mapping to the CCS4 gene were identified in photosynthetic revertants of the ccs4ccs5 mutants. The suppressor mutations yield changes in the stroma-facing domain of CCS4 that restore holocytochrome f assembly above the residual levels detected in ccs5. Because the CCDA protein accumulation is decreased specifically in the ccs4 mutant, we hypothesize the suppressor mutations enhance the supply of reducing power through CCDA in the absence of CCS5. We discuss the operation of a CCS5-dependent and a CCS5-independent pathway controlling the redox status of the heme-binding cysteines of apocytochrome f.

Origin and functional diversification of PAS domain, a ubiquitous intracellular sensor.

Signal perception is a key function in regulating biological activities and adapting to changing environments. Per-Arnt-Sim (PAS) domains are ubiquitous sensors found in diverse receptors in bacteria, archaea, and eukaryotes, but their origins, distribution across the tree of life, and extent of their functional diversity are not fully characterized. Here, we show that using sequence conservation and structural information, it is possible to propose specific and potential functions for a large portion of nearly 3 million PAS domains. Our analysis suggests that PAS domains originated in bacteria and were horizontally transferred to archaea and eukaryotes. We reveal that gas sensing via a heme cofactor evolved independently in several lineages, whereas redox and light sensing via flavin adenine dinucleotide and flavin mononucleotide cofactors have the same origin. The close relatedness of human PAS domains to those in bacteria provides an opportunity for drug design by exploring potential natural ligands and cofactors for bacterial homologs.

Transmembrane Transcription Regulators Are Widespread in Bacteria and Archaea.

To adapt and proliferate, bacteria must sense and respond to the ever-changing environment. Transmembrane transcription regulators (TTRs) are a family of one-component transcription regulators that respond to extracellular information and influence gene expression from the cytoplasmic membrane. How TTRs function to modulate expression of their target genes while localized to the cytoplasmic membrane remains poorly understood. In part, this is due to a lack of knowledge regarding the prevalence of TTRs among prokaryotes. Here, we show that TTRs are highly diverse and prevalent throughout bacteria and archaea. Our work demonstrates that TTRs are more common than previously appreciated and are enriched within specific bacterial and archaeal phyla and that many TTRs have unique transmembrane region properties that can facilitate association with detergent-resistant membranes. IMPORTANCE One-component signal transduction systems are the major class of signal transduction systems among bacteria and are commonly cytoplasmic. TTRs are a group of unique one-component signal transduction systems that influence transcription from the cytoplasmic membrane. TTRs have been implicated in a wide array of biological pathways critical for both pathogens and human commensal organisms but were considered to be rare. Here, we demonstrate that TTRs are in fact highly diverse and broadly distributed in bacteria and archaea. Our findings suggest that transcription factors can access the chromosome and influence transcription from the membrane in both archaea and bacteria. This study challenges thus the commonly held notion that signal transduction systems require a cytoplasmic transcription factor and highlights the importance of the cytoplasmic membrane in directly influencing signal transduction.

The structural analysis of the periplasmic domain of Sinorhizobium meliloti chemoreceptor McpZ reveals a novel fold and suggests a complex mechanism of transmembrane signaling.

Chemotaxis is a fundamental process whereby bacteria seek out nutrient sources and avoid harmful chemicals. For the symbiotic soil bacterium Sinorhizobium meliloti, the chemotaxis system also plays an essential role in the interaction with its legume host. The chemotactic signaling cascade is initiated through interactions of an attractant or repellent compound with chemoreceptors or methyl-accepting chemotaxis proteins (MCPs). S. meliloti possesses eight chemoreceptors to mediate chemotaxis. Six of these receptors are transmembrane proteins with periplasmic ligand-binding domains (LBDs). The specific functions of McpW and McpZ are still unknown. Here, we report the crystal structure of the periplasmic domain of McpZ (McpZPD) at 2.7 Å resolution. McpZPD assumes a novel fold consisting of three concatenated four-helix bundle modules. Through phylogenetic analyses, we discovered that this helical tri-modular domain fold arose within the Rhizobiaceae family and is still evolving rapidly. The structure, offering a rare view of a ligand-free dimeric MCP-LBD, reveals a novel dimerization interface. Molecular dynamics calculations suggest ligand binding will induce conformational changes that result in large horizontal helix movements within the membrane-proximal domains of the McpZPD dimer that are accompanied by a 5 Å vertical shift of the terminal helix toward the inner cell membrane. These results suggest a mechanism of transmembrane signaling for this family of MCPs that entails both piston-type and scissoring movements. The predicted movements terminate in a conformation that closely mirrors those observed in related ligand-bound MCP-LBDs.

Amine recognizing domain in diverse receptors from bacteria and archaea evolved from the universal amino acid sensor.

Bacteria contain many different receptor families that sense different signals permitting an optimal adaptation to the environment. A major limitation in microbiology is the lack of information on the signal molecules that activate receptors. Due to a significant sequence divergence, the signal recognized by sensor domains is only poorly reflected in overall sequence identity. Biogenic amines are of central physiological relevance for microorganisms and serve for example as substrates for aerobic and anaerobic growth, neurotransmitters or osmoprotectants. Based on protein structural information and sequence analysis, we report here the identification of a sequence motif that is specific for amine-sensing dCache sensor domains (dCache_1AM). These domains were identified in more than 13,000 proteins from 8,000 bacterial and archaeal species. dCache_1AM containing receptors were identified in all major receptor families including sensor kinases, chemoreceptors, receptors involved in second messenger homeostasis and Ser/Thr phosphatases. The screening of compound libraries and microcalorimetric titrations of selected dCache_1AM domains confirmed their capacity to specifically bind amines. Mutants in the amine binding motif or domains that contain a single mismatch in the binding motif, had either no or a largely reduced affinity for amines, illustrating the specificity of this motif. We demonstrate that the dCache_1AM domain has evolved from the universal amino acid sensing domain, providing novel insight into receptor evolution. Our approach enables precise "wet"-lab experiments to define the function of regulatory systems and thus holds a strong promise to address an important bottleneck in microbiology: the identification of signals that stimulate numerous receptors.

Three unrelated chemoreceptors provide Pectobacterium atrosepticum with a broad-spectrum amino acid sensing capability.

Amino acids are important nutrients and also serve as signals for diverse signal transduction pathways. Bacteria use chemoreceptors to recognize amino acid attractants and to navigate their gradients. In Escherichia coli two likely paralogous chemoreceptors Tsr and Tar detect 9 amino acids, whereas in Pseudomonas aeruginosa the paralogous chemoreceptors PctA, PctB and PctC detect 18 amino acids. Here, we show that the phytobacterium Pectobacterium atrosepticum uses the three non-homologous chemoreceptors PacA, PacB and PacC to detect 19 proteinogenic and several non-proteinogenic amino acids. PacB recognizes 18 proteinogenic amino acids as well as 8 non-proteinogenic amino acids. PacB has a ligand preference for the three branched chain amino acids L-leucine, L-valine and L-isoleucine. PacA detects L-proline next to several quaternary amines. The third chemoreceptor, PacC, is an ortholog of E. coli Tsr and the only one of the 36 P. atrosepticum chemoreceptors that is encoded in the cluster of chemosensory pathway genes. Surprisingly, in contrast to Tsr, which primarily senses serine, PacC recognizes aspartate as the major chemoeffector but not serine. Our results demonstrate that bacteria use various strategies to sense a wide range of amino acids and that it takes more than one chemoreceptor to achieve this goal.

The importance of cache domains in α2δ proteins and the basis for their gabapentinoid selectivity.

In this hybrid review, we have first collected and reviewed available information on the structure and function of the enigmatic cache domains in α2δ proteins. These are organized into two double cache (dCache_1) domains, and they are present in all α2δ proteins. We have also included new data on the key function of these domains with respect to amino acid and gabapentinoid binding to the universal amino acid-binding pocket, which is present in α2δ-1 and α2δ-2. We have now identified the reason why α2δ-3 and α2δ-4 do not bind gabapentinoid drugs or amino acids with bulky side chains. In relation to this, we have determined that the bulky amino acids Tryptophan and Phenylalanine prevent gabapentin from inhibiting cell surface trafficking of α2δ-1. Together, these novel data shed further light on the importance of the cache domains in α2δ proteins.

Emergence of an Auxin Sensing Domain in Plant-Associated Bacteria.

Bacteria have evolved a sophisticated array of signal transduction systems that allow them to adapt their physiology and metabolism to changing environmental conditions. Typically, these systems recognize signals through dedicated ligand binding domains (LBDs) to ultimately trigger a diversity of physiological responses. Nonetheless, an increasing number of reports reveal that signal transduction receptors also bind antagonists to inhibit responses mediated by agonists. The mechanisms by which antagonists block the downstream signaling cascade remain largely unknown. To advance our knowledge in this field, we used the LysR-type transcriptional regulator AdmX as a model. AdmX activates the expression of an antibiotic biosynthetic cluster in the rhizobacterium Serratia plymuthica. AdmX specifically recognizes the auxin phytohormone indole-3-acetic acid (IAA) and its biosynthetic intermediate indole-3-pyruvic acid (IPA) as signals. However, only IAA, but not IPA, was shown to regulate antibiotic production in S. plymuthica. Here, we report the high-resolution structures of the LBD of AdmX in complex with IAA and IPA. We found that IAA and IPA compete for binding to AdmX. Although IAA and IPA binding does not alter the oligomeric state of AdmX, IPA binding causes a higher degree of compactness in the protein structure. Molecular dynamics simulations revealed significant differences in the binding modes of IAA and IPA by AdmX, and the inspection of the three-dimensional structures evidenced differential agonist- and antagonist-mediated structural changes. Key residues for auxin binding were identified and an auxin recognition motif defined. Phylogenetic clustering supports the recent evolutionary emergence of this motif specifically in plant-associated enterobacteria. IMPORTANCE Although antagonists were found to bind different bacterial signal transduction receptors, we are still at the early stages of understanding the molecular details by which these molecules exert their inhibitory effects. Here, we provide insight into the structural changes resulting from the binding of an agonist and an antagonist to a sensor protein. Our data indicate that agonist and antagonist recognition is characterized by small conformational differences in the LBDs that can be efficiently transmitted to the output domain to modulate the final response. LBDs are subject to strong selective pressures and are rapidly evolving domains. An increasing number of reports support the idea that environmental factors drive the evolution of sensor domains. Given the recent evolutionary history of AdmX homologs, as well as their narrow phyletic distribution within plant-associated bacteria, our results are in accordance with a plant-mediated evolutionary process that resulted in the emergence of receptor proteins that specifically sense auxin phytohormones.

Diverse Sensory Repertoire of Paralogous Chemoreceptors Tlp2, Tlp3, and Tlp4 in Campylobacter jejuni.

Campylobacter jejuni responds to extracellular stimuli via transducer-like chemoreceptors (Tlps). Here, we describe receptor-ligand interactions of a unique paralogue family of dCache_1 (double Calcium channels and chemotaxis) chemoreceptors: Tlp2, Tlp3, and Tlp4. Phylogenetic analysis revealed that Tlp2, Tlp3, and Tlp4 receptors may have arisen through domain duplications, followed by a divergent evolutionary drift, with Tlp3 emerging more recently, and unexpectedly, responded to glycans, as well as multiple organic and amino acids with overlapping specificities. All three Tlps interacted with five monosaccharides and complex glycans, including Lewis's antigens, P antigens, and fucosyl GM1 ganglioside, indicating a potential role in host-pathogen interactions. Analysis of chemotactic motility of single, double, and triple mutants indicated that these chemoreceptors are likely to work together to balance responses to attractants and repellents to modulate chemotaxis in C. jejuni. Molecular docking experiments, in combination with saturation transfer difference nuclear magnetic resonance spectroscopy and competition surface plasmon resonance analysis, illustrated that the ligand-binding domain of Tlp3 possess one major binding pocket with two overlapping, but distinct binding sites able to interact with multiple ligands. A diverse sensory repertoire could provide C. jejuni with the ability to modulate responses to attractant and repellent signals and allow for adaptation in host-pathogen interactions. IMPORTANCE Campylobacter jejuni responds to extracellular stimuli via transducer-like chemoreceptors (Tlps). This remarkable sensory perception mechanism allows bacteria to sense environmental changes and avoid unfavorable conditions or to maneuver toward nutrient sources and host cells. Here, we describe receptor-ligand interactions of a unique paralogue family of chemoreceptors, Tlp2, Tlp3, and Tlp4, that may have arisen through domain duplications, followed by a divergent evolutionary drift, with Tlp3 emerging more recently. Unlike previous reports of ligands interacting with sensory proteins, Tlp2, Tlp3, and Tlp4 responded to many types of chemical compounds, including simple and complex sugars such as those present on human blood group antigens and gangliosides, indicating a potential role in host-pathogen interactions. Diverse sensory repertoire could provide C. jejuni with the ability to modulate responses to attractant and repellent signals and allow for adaptation in host-pathogen interactions.