Abstract
Bacterial pathogens rely on a complex network of regulatory proteins to adapt to hostile and nutrient-limiting host environments. The phosphoenolpyruvate phosphotransferase system (PTS) is a conserved pathway in bacteria that couples transport of sugars with phosphorylation to monitor host carbohydrate availability. A family of structurally homologous PTS-regulatory-domain-containing virulence regulators (PCVRs) has been recognized in divergent bacterial pathogens, including Streptococcus pyogenes Mga and Bacillus anthracis AtxA. These paradigm PCVRs undergo phosphorylation, potentially via the PTS, which impacts their dimerization and their activity. Recent work with predicted PCVRs from Streptococcus pneumoniae (MgaSpn) and Enterococcus faecalis (MafR) suggest they interact with DNA like nucleoid-associating proteins. Yet, Mga binds to promoter sequences as a homo-dimeric transcription factor, suggesting a bi-modal interaction with DNA. High-resolution crystal structures of 3 PCVRs have validated the domain structure, but also raised additional questions such as how ubiquitous are PCVRs, is PTS-mediated histidine phosphorylation via potential PCVRs widespread, do specific sugars signal through PCVRs, and do PCVRs interact with DNA both as transcription factors and nucleoid-associating proteins? Here, we will review known and putative PCVRs based on key domain and functional characteristics and consider their roles as both transcription factors and possibly chromatin-structuring proteins.
Highlights
Nutrient acquisition is a major challenge for bacterial pathogens during infection
The phosphotransferase system (PTS)-pathway is a conserved system in Gram-positive bacteria that couples the import of sugars while simultaneously informing the bacteria of their respective availability and PRDcontaining regulatory proteins are the major mediators of these signals
It is clear that there is a class of proteins that can be defined as PTS-regulatory-domain-containing virulence regulators (PCVRs), that exist in diverse Gram-positive pathogens and contain structural homology with classical PTS-regulatory domain (PRD)-containing regulators
Summary
Nutrient acquisition is a major challenge for bacterial pathogens during infection. Energy-rich carbon resources are in high demand for both the invading pathogen as well as the host. The genes encoding AcpA and AcpB are located in close proximity to one another (Vietri et al, 1995; Drysdale et al, 2004), and have been described as PCVRs based on their sequence similarity with AtxA and their function (Raynor et al, 2018) Both AcpA and AcpB contain two N-terminal HTH putative DNAbinding domains as well as two core LicT-like PRDs and one Cterminal EIIBGat-like domain (Raynor et al, 2018) (Figure 2). MgaSpn H391, H320, and H318 align with H379, H324, and H342 of AtxA, Mga, and MtlR, respectively, all of which have been shown to be involved in modulating protein activity (Tsvetanova et al, 2007; Hondorp et al, 2013; Joyet et al, 2013) These overlaps in histidine residues would indicate that MgaSpn may still retain the capacity to undergo PTSmediated phosphorylation. Further studies must be performed in order to better understand how, if at all, the PTS directly modulates PCVRs and which carbon sources act as signals to sense host microenvironments in divergent bacterial species
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