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) 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.
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Acknowledgements
We thank M. S. Smeltzer for his critical reading of this manuscript. Intensity data collected at the Stanford Synchrotron Radiation Laboratory (SSRL) was carried out under the SSRL biotechnology program, which is supported by the National Institutes of Health (NIH), National Center for Research Resources, Biomedical Technology Program, and by the Department of Energy, Office of Biological and Environmental Research. M.A.S. is a Burroughs Wellcome Career Awardee. This work was supported by the NIH Oregon Health Sciences Foundation (R.G.B.).
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Schumacher, M., Hurlburt, B. & Brennan, R. Crystal structures of SarA, a pleiotropic regulator of virulence genes in S. aureus. Nature 409, 215–219 (2001). https://doi.org/10.1038/35051623
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DOI: https://doi.org/10.1038/35051623
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