![]() One consists of a sensor histidine kinase (Hk2/BB0764) and response regulator (Rrp2/BB0763), both of which are predicted to localize to the cytoplasm. The genome of Borrelia burgdorferi, the Lyme disease spirochete, encodes two TCSs in addition to the CheA and CheY orthologs associated with chemotaxis ( 24, 31). Although examples of cross talk have been reported, bacteria have evolved multiple mechanisms to prevent inadvertent signaling between unrelated HK and RR components ( 69). Once activated, the RR effector domain elicits an appropriate response, typically by altering transcription of specific genes or allosteric regulation of target proteins ( 26). The cognate RR then catalyzes the transfer of the phosphoryl group from the phosphorylated His (His∼P) to an Asp residue within its own REC domain ( 29). In its simplest form, regulation via TCSs begins with the binding of a specific ligand by the HK sensor domain, which in turn induces a conformation change promoting autophosphorylation of a His residue within the kinase core ( 29). RR proteins typically are comprised of a conserved receiver (REC) domain and an effector domain ( 26, 29). The majority of TCS HKs consist of a variable extracytoplasmic sensor domain and conserved cytoplasmic kinase core containing catalytic ATP-binding (CA) and dimerization/histidine phosphotransfer (DHp) domains ( 29). Typically, TCSs are composed of sensor histidine kinase (HK) and response regulator (RR) components, with the genes encoding a particular TCS frequently being cotranscribed ( 25, 29). Two-component signal transduction systems (TCSs) are principal mechanisms by which bacteria survey and adapt to perturbations in their surroundings ( 29, 44). In contrast to the Rrp2/RpoN/RpoS pathway, which is active only within feeding nymphs, the Hk1/Rrp1 TCS is essential for survival during both larval and nymphal blood meals. Once activated, Rrp1 directs the synthesis of cyclic dimeric GMP (c-di-GMP), which, in turn, modulates the expression and/or activity of gene products required for survival within feeding ticks. We hypothesize that the phosphorelay between Hk1 and Rrp1 is initiated by the binding of feeding-specific ligand(s) to Hk1 sensor domain D1 and/or D2. Extensive characterization of the resulting mutants revealed a dramatic phenotype whereby Hk1-deficient spirochetes are virulent in mice and able to migrate out of the bite site during feeding but are killed within the midgut following acquisition. To investigate the role of Hk1 during the enzootic cycle, we inactivated this gene in two virulent backgrounds. In addition to its REC domain, Rrp1 contains a GGDEF motif characteristic of diguanylate cyclases. ![]() Hk1 is composed of two periplasmic sensor domains (D1 and D2), followed by conserved cytoplasmic histidine kinase core, REC, and Hpt domains. The other TCS consists of a hybrid histidine kinase, Hk1, and the response regulator Rrp1. Genes within the Rrp2/RpoN/RpoS regulon function to promote tick transmission and early infection. While the contribution of Hk2 remains unclear, Rrp2 is part of a regulatory pathway involving the spirochete's alternate sigma factors, RpoN and RpoS. One is comprised of a histidine kinase, Hk2, and the response regulator Rrp2. Borrelia burgdorferi encodes only two TCS. Two-component systems (TCS) are principal mechanisms by which bacteria adapt to their surroundings. ![]()
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