Global regulation of virulence determinants in Staphylococcus Aureus by the SarA protein family

Abstract

In S. aureus, the production of virulence determinants such as cell wall adhesins and exotoxins during the growth cycle is controlled by global regulators such as SarA and agr. Genomic scan reveals 16 two-component regulatory systems (e.g. agr and sae) as well as a family of SarA homologs in S. aureus. We call the SarA homologs the SarA protein family. Many of the members in this protein family are either small basic proteins (<153 residues) or two-domain proteins in which a single domain shares sequence similarity to each of the small basic proteins. Recent crystal structures of SarR and SarA reveal dimeric structures for these proteins. Because of its structure and unique mode of DNA binding, SarR, and possibly other SarA family members, may belong to a new functional class of the winged-helix family, accommodating long stretch of DNA with bending points. Based on sequence homology, we hypothesize that the SarA protein family may entail homologous structures with similar DNA-binding motifs but divergent activation domains. An understanding of how these regulators interact with each other in vivo and how they sense environmental signals to control virulence gene expression (e.g. alpha-hemolysin) will be important to our eventual goal of disrupting the regulatory network.

Regulation and characterization of rot transcription in Staphylococcus aureus

“…The fact that S. aureus exhibits complex patterns of protein expression in response to various environmental conditions (Arvidson & Tegmark, 2001;Cheung & Zhang, 2002;Lowy, 1998;Novick, 2003;Projan & Novick, 1997) is consistent with the notion that large numbers of complex regulatory systems coordinate expression of most virulence factors that are involved in the infectious processes. The transcriptional regulators, particularly the SarA protein family, are emerging as an important regulatory system for potential interference and therefore control of S. aureus infections.…”

“…SarA, SarR, MgrA), while the larger proteins with two homologous domains are monomers (e.g. SarS) and are also homologous to the wingedhelix family of transcription factors with unique variations (Cheung & Zhang, 2002;Liu et al, 2001Liu et al, , 2006Manna & Cheung, 2006a). While many of these genes either activate or repress the expression of virulence and regulatory genes, the exact mode of regulation is not well defined.…”

“…The expression of many of these virulence genes is coordinately controlled by regulatory loci, such as two-component regulatory systems (agr, saeRS, srrAB and arlSR) and global transcriptional regulators (sarA, sigB, sarA paralogues, tcaRA, etc.) (Arvidson & Tegmark, 2001;Cheung et al, 1992;Cheung & Zhang, 2002;Luong et al, 2003;, 2006aManna et al, 2004;McNamara et al, 2000;McNamara & Bayer, 2005;Novick, 2003;Projan & Novick, 1997;Truong-Bolduc et al, 2003).…”

“…SarA is the first characterized member of the SarA family; others characterized are SarR , SarS (also called SarH1) Tegmark et al, 2000), SarT , Rot (McNamara et al, 2000), SarU (Manna & Cheung, 2003), SarV (Manna et al, 2004), MgrA (Luong et al, 2003;Truong-Bolduc et al, 2003) and SarX (Manna & Cheung, 2006b). The SarA family represents a group of DNA-binding proteins that share homology with each other (20-45 % identity and 45-65 % similarity to SarA protein) as well as with the MarR family of proteins involved in regulating multi-drug resistance in Gram-negative bacteria (Cheung & Zhang, 2002). Although some members of the sarA family of genes are only partially characterized, the known attributes of nine sarA-like genes suggest that most SarA paralogues function as both repressors and activators.…”

Regulation of Staphylococcal Superantigen-Like Gene, ssl8, Expression in Staphylococcus aureus strain, RN6390

“…[1][2][3] These toxins are synthesized preferentially during the transition between exponential and stationary growth phases. 4 Among its large number of secreted toxins, is a group of staphylococcal superantigenlike (SSL) proteins encoded by 11 ssl (formerly known as staphylococcal exotoxin-like or set) genes.…”