Structure and Mechanism of Action of Sda, an Inhibitor of the Histidine Kinases that Regulate Initiation of Sporulation in Bacillus subtilis

Rowland, Susan; Burkholder, William F.; Cunningham, Kathryn A.; Maciejewski, Mark W.; Grossman, Alan D.; King, Glenn F.

doi:10.1016/s1097-2765(04)00084-x

Cited by 115 publications

(189 citation statements)

References 42 publications

(2 reference statements)

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“…For example, in B. subtilis the small proteins Sda and KipI each bind to the specificity residues of the sporulation kinases, thereby blocking phosphotransfer to their cognate partner, Spo0F, and preventing the initiation of spore formation [32][33][34]. These small inhibitors represent exciting templates for future protein design efforts and the development of specific inhibitors of other two-component systems.…”

Section: Identification and Characterization Of Specificity Residuesmentioning

confidence: 99%

Determinants of specificity in two-component signal transduction

Podgornaia

Laub

2013

Current Opinion in Microbiology

128

133

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Maintaining the faithful flow of information through signal transduction pathways is critical to the survival and proliferation of organisms. This problem is particularly challenging as many signaling proteins are part of large, paralogous families that are highly similar at the sequence and structural levels, increasing the risk of unwanted cross-talk. To detect environmental signals and process information, bacteria rely heavily on two-component signaling systems comprised of sensor histidine kinases and their cognate response regulators. Although most species encode dozens of these signaling pathways, there is relatively little cross-talk, indicating that individual pathways are well insulated and highly specific. Here, we review the molecular mechanisms that enforce this specificity. Further, we highlight recent studies that have revealed how these mechanisms evolve to accommodate the introduction of new pathways by gene duplication.3

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Section: Identification and Characterization Of Specificity Residuesmentioning

confidence: 99%

Determinants of specificity in two-component signal transduction

Podgornaia

Laub

2013

Current Opinion in Microbiology

128

133

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“…Two relatively wellcharacterized inhibitors of this class are Sda and KipI from the endospore-forming bacterium Bacillus subtilis (Wang et al, 1997;Burkholder et al, 2001;Rowland et al, 2004). Sda and KipI inhibit sporulation of B. subtilis by inhibiting one or both of the histidine kinases required to initiate spore development under nutrient-limiting conditions, KinA and KinB.…”

Section: Introductionmentioning

confidence: 99%

“…Sda and KipI appear to inhibit KinA by similar mechanisms, although they share no similarity in sequence or structure (Wang et al, 1997;Rowland et al, 2004;Jacques et al, 2008). As with other histidine kinases belonging to the same superfamily as KinA, the kinase domain of KinA consists of two subdomains, a dimerization/histidine-phosphotransfer (DHp) domain that contains the conserved histidine residue that is the site of autophosphorylation and a catalytic ATP-binding (CA) domain.…”

Section: Introductionmentioning

confidence: 99%

“…Spo0F interacts with the phosphorylated DHp domain and promotes the transfer of phosphate from the histidyl side-chain of KinA to a conserved aspartyl residue in Spo0F. Sda and KipI both bind the DHp domain of KinA (Rowland et al, 2004;Whitten et al, 2007;Jacques et al, 2008) and inhibit both autophosphorylation and the reverse reaction, the transfer of phosphate from KinA~P to ADP (Wang et al, 1997;Rowland et al, 2004). Even though Sda and KipI both bind KinA~P, as evidenced by their ability to inhibit the transfer of phosphate to ADP, neither protein has been observed to inhibit the transfer of phosphate from KinA~P to Spo0F (Wang et al, 1997;Rowland et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F

Cunningham

Burkholder²

2009

Molecular Microbiology

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SummaryHistidine kinases are widely used by bacteria, fungi and plants to sense and respond to changing environmental conditions. Signals in addition to those directly sensed by the kinase are often integrated by proteins that fine-tune the biological response by modulating the activity of the kinase or its targets. The Bacillus subtilis histidine kinase KinA promotes the initiation of sporulation when nutrients are limiting, but sporulation can be delayed by two inhibitors of KinA, Sda (when DNA replication is perturbed) or KipI (under unknown conditions). We have identified residues in the dimerization/histidinephosphotransfer (DHp) domain of KinA that are functionally important for inhibition by Sda and KipI and overlapping surface-exposed residues that lie close to or comprise the Sda binding site. Sda inhibits the intermolecular transfer of phosphate from the catalytic ATP-binding (CA) domain of KinA to the autophosphorylation site in the DHp domain when the domains are split into separate polypeptides, either by steric hindrance or by altering the conformation of the DHp domain. Sda also slows the rate of phosphotransfer from KinA~P to its target, Spo0F, consistent with our finding that a KinA residue important for Sda function overlaps with the predicted Spo0F binding site on KinA.

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“…The activity of KinA is subject to inhibition by two other proteins: Sda and KipI (6,32,39). Both proteins bind to KinA, thereby blocking autophosphorylation.…”

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confidence: 99%

Phosphorylation of Spo0A by the Histidine Kinase KinD Requires the Lipoprotein Med in Bacillus subtilis

2011

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The response regulatory protein Spo0A of Bacillus subtilis is activated by phosphorylation by multiple histidine kinases via a multicomponent phosphorelay. Here we present evidence that the activity of one of the kinases, KinD, depends on the lipoprotein Med, a mutant of which has been known to cause a cannibalism phenotype. We show that the absence of Med impaired and the overproduction of Med stimulated the transcription of two operons (sdp and skf) involved in cannibalism whose transcription is known to depend on Spo0A in its phosphorylated state (Spo0AϳP). Further, these effects of Med were dependent on KinD but not on kinases KinA, KinB, and KinC. Additionally, we show that deletion or overproduction of Med impaired or enhanced, respectively, biofilm formation and that these effects, too, depended specifically on KinD. Finally, we report that overproduction of Med bypassed the dominant negative effect on transcription of sdp of a truncated KinD retaining the transmembrane segments but lacking the kinase domain. We propose that Med directly or indirectly interacts with KinD in the cytoplasmic membrane and that this interaction is required for KinDdependent phosphorylation of Spo0A.

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Structure and Mechanism of Action of Sda, an Inhibitor of the Histidine Kinases that Regulate Initiation of Sporulation in Bacillus subtilis

Cited by 115 publications

References 42 publications

Determinants of specificity in two-component signal transduction

Determinants of specificity in two-component signal transduction

The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F

Phosphorylation of Spo0A by the Histidine Kinase KinD Requires the Lipoprotein Med in Bacillus subtilis

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