Crystal structures of SarA, a pleiotropic regulator of virulence genes in S. aureus

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) locus1,2,3. 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 promoter4. Subsequent DNA-binding studies have revealed that SarA binds readily to multiple AT-rich sequences of variable lengths4,5,6,7,8,9,10,11. Here we describe the crystal structure of SarA and a SarA–DNA complex at resolutions of 2.50 Å and 2.95 Å, respectively. SarA has a fold consisting of a four-helix core region and ‘inducible regions’ comprising a β-hairpin and a carboxy-terminal loop. On binding DNA, the inducible regions undergo marked conformational changes, becoming part of extended and distorted α-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.