Many Bacterial Responses Are Controlled by Two Component Regulatory Systems

As we've just seen, control of the E. coli glnA gene depends on two proteins, NtrC and NtrB. Such two-component regulatory systems control many responses of bacteria to changes in their environment. Another example involves the E. coli proteins PhoR and PhoB, which regulate transcription in response to the concentration of free phosphate. PhoR is a transmembrane protein, located in the inner (plasma) membrane, whose periplasmic domain binds phosphate with moderate affinity and whose cytosolic domain has protein kinase activity; PhoB is a cytosolic protein.

Large protein pores in the E. coli outer membrane allow ions to diffuse freely between the external environment and the periplasmic space. Consequently, when the phosphate concentration in the environment falls, it also falls in the periplasmic space, causing phosphate to dissociate from the PhoR periplasmic domain, as depicted in Figure 4-18. This causes a conformational change in the PhoR cytoplasmic domain that activates its protein kinase activity. The activated PhoR initially transfers a 7-phosphate from ATP to a histi-dine side chain in the PhoR kinase domain itself. The same phosphate is then transferred to a specific aspartic acid side chain in PhoB, converting PhoB from an inactive to an active transcriptional activator. Phosphorylated, active PhoB then induces transcription from several genes that help the cell cope with low phosphate conditions.

Many other bacterial responses are regulated by two proteins with homology to PhoR and PhoB. In each of these regulatory systems, one protein, called a sensor, contains a transmitter domain homologous to the PhoR protein kinase domain. The transmitter domain of the sensor protein is regulated by a second unique protein domain (e.g., the periplas-mic domain of PhoR) that senses environmental changes. The second protein, called a response regulator, contains a

► FIGURE 4-18 The PhoR/PhoB two-component regulatory system in E. coli. In response to low phosphate concentrations in the environment and periplasmic space, a phosphate ion dissociates from the periplasmic domain of the inactive sensor protein PhoR. This causes a conformational change that activates a protein kinase transmitter domain in the cytosolic region of PhoR. The activated transmitter domain transfers an ATP y phosphate to a conserved histidine in the transmitter domain. This phosphate is then transferred to an aspartic acid in the receiver domain of the response regulator PhoB. Several PhoB proteins can be phosphorylated by one activated PhoR. Phosphorylated PhoB proteins then activate transcription from genes encoding proteins that help the cell to respond to low phosphate, including phoA, phoS, phoE, and ugpB.

PhoR

sensor (inactive)

PhoR

sensor (active)

Periplasmic space

PhoR

sensor (active)

PhoR

sensor (inactive)

PhoB response regulator (inactive)

PhoB response regulator (active)

Cytoplasm

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