[Frontiers in Bioscience 7, d1825-1842, August 1, 2002]

GLOBAL REGULATION OF VIRULENCE DETERMINANTS IN STAPHYLOCOCCUS AUREUS BY THE SarA PROTEIN FAMILY

Ambrose L Cheung 1 and Gongyi Zhang 2

1 Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755, 2 Department of Immunology, National Jewish Medical and Research Center and Department of Pharmacology, University of Colorado Medical School, Denver, CO 80286

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Review
3.1. Global Regulation of virulence determinants during in vitro growth
3.2. Regulation of virulence determinants by two-component regulatory systems in S. aureus
3.2.1. The agr locus
3.2.2. The saeRS locus
3.2.3. The lytRS locus
3.2.4. The arlRS locus
3.2.5. The srrAB (srhSR) locus
3.2.6. The yycFG locus
3.3.Regulation of virulence determinants by the SarA protein family
3.3.1. The sarA locus
3.3.2. The sarR locus
3.3.3. The sarT locus
3.3.4. The sarS (sarH1) locus
3.3.5. The sarU and sarY loci
3.3.6. Other sarA homologs
3.4. The crystal structures of SarR and SarA and their implications on the SarA protein family
3.5. Environmental and host factors in global regulation of virulence determinants
3.5.1. The role of environmental factors in global regulation
3.5.2. The role of host factors in global regulation
3.6. The role of global regulators in virulence
3.7. The role of sarA and agr in apoptosis
4. Perspectives
5. Acknowledgements

1. 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. a-hemolysin) will be important to our eventual goal of disrupting the regulatory network.