Signal Transduction via the Minireview Multi-Step Phosphorelay : Not Necessarily a Road Less Traveled

four-step His-Asp-His-Asp phosphorelay. Burbulys et Signal Transduction by Two-Component al. (1991) reported the first known phosphorelay built Regulatory Systems from sensor kinase and response regulator family memAll living cells must sense changes in their environment bers. This pathway, which governs initiation of sporulaand respond appropriately. To meet this need, prokarytion in Bacillus subtilis, involves a chain of four proteins otic organisms commonly employ a sophisticated signal through which a phosphoryl group is transferred before transduction strategy knownas the two-component regultimately activating the Spo0A transcriptional regulator ulatory system (reviewed in Parkinson, 1993; Hoch and (Figure 2A). The relay begins with the activation and Silhavy, 1995). This signaling mechanism is ubiquitous concomitant autophosphorylation of one of three sensor in bacteria, and homologous pathways have recently kinases, KinA, KinB, or KinC. The phosphoryl group is been identified in several eukaryotic organisms as well, then transferred to an aspartate residue in Spo0F, a including Saccharomyces cerevisiae, Arabidopsis thaliresponse regulator that is comprised entirely of a conana, Neurospora crassa, and Dictyostelium discoideum served receiver domain. Spo0F serves as a phosphodo(see Alex et al., 1996, and references therein). This mininor for the next link in the chain, Spo0B, which shares review focuses on an emerging class of complex signalno sequence similarity with sensorkinases, butnonetheing pathways built from two-component circuit eleless appears to be phosphorylated on a histidine resiments, the multi-step His-Asp phosphorelay. due. Finally, the phosphoryl group completes its course The prototypical two-component pathway is comby transfer to an aspartate in Spo0A. The sporulation prised of two proteins: a histidine protein kinase, also initiation pathway of B. subtilis remained the only charcalled a sensor kinase, and a response regulator (Figure acterized example of a His-Asp-His-Asp phosphorelay 1). The N-terminal portion of the histidine protein kinase for several years. There have now been several recent functions as an input domain, detecting environmental reports of similar or related circuits in a variety of twostimuli directly or interacting with an upstream receptor. component pathways (Tsuzuki et al., 1995; Uhl and At the C-terminal end of the protein is the transmitter Miller, 1996; Posas et al., 1996, this issue). module. This domain is generally about 240 amino acids The BvgS-BvgA two-component system modulates long and contains several blocks of residues that are the transcriptional regulation of virulence factors in Borconservedamonghistidineproteinkinases.Oneofthese, detella pertussis. In this pathway, the first three steps of termed the H box, includes a histidine residue at which the four-step phosphorelay occur within a single protein, the protein autophosphorylates using the g-phosphoryl BvgS (Uhl and Miller, 1996). BvgS resides in the cytogroup of ATP. The G1 and G2 boxes are glycine-rich plasmic membrane and contains both a transmitter sequences that bear resemblance to the nucleotidemodule and a receiver module, as well as a C-terminal binding motifs of other proteins. The specific functions domain that is characteristic of a family of signaling of the conserved F and N boxes are not readily apparent proteins with similar architecture and, perhaps, phosby inspection of their sequences, but are presumably phorelay patterns. One feature of the C-terminal domain involved in the catalytic activity of the protein. that is shared with all known members of the BvgS family The response regulator has a receiver domain, gener(which includes the bacterial proteins ArcB, BarA, EvgS, ally at its N-terminus, which is approximately 120 amino