title: Crystal structures of SarA, a pleiotropic regulator of virulence genes in S. aureus.
abstract: Staphylococcus aureus is a major human pathogen, the potency of which can be attributed to the regulated expression of an impressive array of virulence determinants. A key pleiotropic transcriptional regulator of these virulence factors is SarA, which is encoded by the sar (staphylococcal accessory regulator) locus. SarA was characterized initially as an activator of a second virulence regulatory locus, agr, through its interaction with a series of heptad repeats (AGTTAAG) within the agr promoter. Subsequent DNA-binding studies have revealed that SarA binds readily to multiple AT-rich sequences of variable lengths. Here we describe the crystal structure of SarA and a SarA-DNA complex at resolutions of 2.50 A and 2.95 A, respectively. SarA has a fold consisting of a four-helix core region and 'inducible regions' comprising a beta-hairpin and a carboxy-terminal loop. On binding DNA, the inducible regions undergo marked conformational changes, becoming part of extended and distorted alpha-helices, which encase the DNA. SarA recognizes an AT-rich site in which the DNA is highly overwound and adopts a D-DNA-like conformation by indirect readout. These structures thus provide insight into SarA-mediated transcription regulation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Schumacher
authors.forename: B K
authors.initials: BK
authors.lastname: Hurlburt
authors.forename: R G
authors.initials: RG
authors.lastname: Brennan
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004269:DNA, Bacterial / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000737:chemistry* / Q000235:genetics / Q000472:pathogenicity; D015534:Trans-Activators; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; C088021:SarA protein, bacterial; D015534:Trans-Activators