Department of Biology, Indiana University, Bloomington, IN 47405, USA
Correspondence
Malcolm E. Winkler
(mwinkler{at}bio.indiana.edu)
Two component regulatory systems (TCSs) are found in all prokaryotes except mycoplasmas (Fraser et al., 1995; Himmelreich et al., 1996
). They play critical roles in sensing and responding to environmental conditions and in bacterial pathogenesis (Hoch, 2000
; Inouye & Dutta, 2003
; Stock et al., 2000
). TCSs consist of a sensor histidine kinase protein, which is usually bound to the bacterial membrane (Wolanin & Stock, 2003
), and a cognate response regulator protein, which often acts as a DNA-binding transcription regulator. Autophosphorylation of the histidine kinase component in response to an environmental signal is followed by phosphoryl transfer to the cognate response regulator, which alters the expression of regulon genes needed to respond to the environmental condition.
Most TCSs are not required for bacteria to grow in the absence of stress in laboratory media (Kobayashi et al., 2001; Oshima et al., 2002
). However, there are exceptions to this generalization in certain Gram-negative bacteria [e.g. Caulobacter crescentus (Quon et al., 1996
)] and in all Gram-positive bacteria with low G+C content in their DNA. Each of these Gram-positive species, which include many important human pathogens (see Table 1
), contains homologues of a single essential TCS, whose histidine kinase and response regulator are designated YycG and YycF, respectively. The gene encoding the YycF response regulator is required for growth of these Gram-positive bacteria under all conditions tested (Echenique & Trombe, 2001
; Fabret & Hoch, 1998
; Martin et al., 1999
; Ng et al., 2003
). The YycG histidine kinase is required for growth of most Gram-positive species tested to date (Fabret & Hoch, 1998
; Martin et al., 1999
) or is conditionally required in Streptococcus pneumoniae depleted for the YycF response regulator (Ng et al., 2003
).
|
All YycG homologues contain a HAMP (linker) domain, a PAS domain, a histidine kinase domain (HisKin, which contains the phosphorylated histidine residue) and an ATPase domain (Fig. 1; Aravind & Ponting, 1999
; Inouye & Dutta, 2003
; Taylor & Zhulin, 1999
). PAS domains of histidine kinases bind cofactors that respond to redox state (Taylor & Zhulin, 1999
) and also act as sites of proteinprotein interactions (Elsen et al., 2003
; Taylor & Zhulin, 1999
; Wang et al., 2001
). Most histidine kinases, including YycG homologues from all Gram-positive species except for Streptococcus, are likely bound to the cytoplasmic membrane by two transmembrane domains that flank an extracytoplasmic loop (Fig. 1a
). These extracytoplasmic loops are thought to play roles in sensing by some histidine kinases (Hoch, 2000
; Wolanin & Stock, 2003
). The extracytoplasmic loops of these YycG homologues are generally large and contain 142154 amino acids (Table 1
). In contrast, the YycG homologues of Streptococcus species contain a single predicted transmembrane domain (Fig. 1b
), and hence lack extracytoplasmic loops (Table 1
). The number of extracellular amino acids that protrude from these single transmembrane domains is small (412 amino acids; Fig. 1b
; Table 1
).
|
The structural and operon differences of the YycFG TCSs of Streptococcus species compared to those of other Gram-positive species suggest important differences in signal transduction. There are clearly two distinct classes of YycG histidine kinases (Fig. 1; Table 1
), which tends to argue against the view that the extracytoplasmic domains of YycG homologues became randomized during evolution (Hoch, 2000
). Moreover, a different subset of associated components (YycJ, YycH and YycI) is associated with each YycG class (Table 1
). These structural differences imply that different signals or subsets of signals may be sensed by YycG homologues in Streptococcus species compared to those sensed in other Gram-positive species. It is noteworthy that Gram-positive species containing YycG histidine kinases with two transmembrane domains flanking large extracytoplasmic loops (Fig. 1a
) and associated YycH and YycI components have the capacity for electron transport, which is absent from all species of Streptococcus, except for Streptococcus agalactiae (Table 1
). Perhaps, the extended extracytoplasmic domain of YycG and the YycH and YycI components sense the redox state of electron transport.
On the other hand, the cytoplasmic PAS domains of all YycG homologues and the associated YycJ components may sense small molecule and cofactor signals that reflect metabolic state, such as those that accumulate during aerobic or anaerobic growth or stress (Nakano & Zuber, 1998; Taylor & Zhulin, 1999
). The metabolisms and physiological niches of different Gram-positive bacteria vary considerably. These differences may be reflected by the different sets of genes regulated by the YycFG TCSs (Dubrac & Msadek, 2004
; Fukuchi et al., 2000
; Howell et al., 2003
; Ng et al., 2003
). It remains to be determined whether the same or different small molecules' signals are sensed by YycG homologues in these disparate species.
Acknowledgements
Supported by research funds from Indiana University Bloomington. Wai-Leung Ng is a predoctoral trainee on grant NIGM-T32GM0775 from the National Institutes of Health of the USA.
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