The SarA protein family of Staphylococcus aureus

Abstract

Staphylococcus aureus is widely appreciated as an opportunistic pathogen, primarily in hospital-related infections. However, recent reports indicate that S. aureus infections can now occur in other wise healthy individuals in the community setting. The success of this organism can be attributed to the large array of regulatory proteins, including the SarA protein family, used to respond to changing microenvironments. Sequence alignment and structural data reveal that the SarA protein family can be divided into three subfamilies: (1) single domain proteins; (2) double domain proteins; (3) MarR homologs. Structural studies have also demonstrated that SarA, SarR, SarS, MgrA and thus possibly all members of this protein family are winged helix proteins with minor variations. Mutagenesis studies of SarA disclose that the winged helix motifs are important for DNA binding and function. Recent progress concerning the functions and plausible mechanisms of regulation of SarA and its homologs are discussed.

Fig. 1

Regulation of virulence determinants in S. aureus by the SarA protein family adapted from Crossley and Archer (Crossley and Archer, 1997). Normally, the synthesis of cell surface adhesins such as fibronectin binding protein A (FnbA) during the exponential phase coincides with the expression of SarA and SaeRS. In transition from exponential to postexponential phase, the synthesis of cell wall proteins is disrupted and the production of extracellular toxins such as a-toxin would begin. This transition corresponds to the maximal expression of SarA and the ensuing activation of agr. SarA expression is repressed by SarA and SarR. SigB, a stress-induced transcription factor, also activates one of the sarA promoter (the P3 promoter). On the other hand, agr is controlled by SarA, a quorum sensing autoinducing peptide, other TCRS (see Table 1), MgrA, SarX and SarU. Activation of agr would lead to up-regulation of another TCRS system called SaeRS and down-regulation of a SarA protein homolog called Rot. This will eventually lead to repression of two gene products called SarT and subsequently SarS. SarT is an activator of SarS, which is a repressor of alpha toxin production and an activator of protein A synthesis, thus explaining the elevated production of α-toxin and repression of protein A upon agr activation. Activation of agr would also result in the amplification of the original signal by activating SarU, which is a positive regulator of agr.

Fig. 2

Comparison of the SarR, SarS and MgrA winged helix structures. The SarR structure is composed of two identical monomers, one in green and the other in yellow. Each monomer is composed of five α-helices and three β-strands. In contrast, SarS is composed of two homologous but non-identical halves connected by a linker region. MgrA has 7 α-helices and three β-strands. There are coiled coil interactions between two α7 helices from the monomers.

Fig. 3

Sequence alignment of members of the SarA protein family. SarA, SarR, SarT and Rot belong to the single domain proteins. Rot is unique for its larger size and an acidic pI. SarS represents a two domain protein, with two homologous halves connected by a linker region. SarS1 and SarS2 represent the N-terminal and C-terminal halves, respectively. MgrA and SarZ are more homologous to the MarR protein family of Gram negative bacteria than to the SarA protein family and thus represent the third subfamily within the SarA protein family. The HTH and the wing regions of the winged helix structures are indicated. The residues (▼) altered by mutagenesis in SarA have been highlighted (Liu et al., 2006).