title: Staphylococcus aureus PerR Is a Hypersensitive Hydrogen Peroxide Sensor using Iron-mediated Histidine Oxidation.
abstract: In many Gram-positive bacteria PerR is a major peroxide sensor whose repressor activity is dependent on a bound metal cofactor. The prototype for PerR sensors, the Bacillus subtilis PerRBS protein, represses target genes when bound to either Mn(2+) or Fe(2+) as corepressor, but only the Fe(2+)-bound form responds to H2O2. The orthologous protein in the human pathogen Staphylococcus aureus, PerRSA, plays important roles in H2O2 resistance and virulence. However, PerRSA is reported to only respond to Mn(2+) as corepressor, which suggests that it might rely on a distinct, iron-independent mechanism for H2O2 sensing. Here we demonstrate that PerRSA uses either Fe(2+) or Mn(2+) as corepressor, and that, like PerRBS, the Fe(2+)-bound form of PerRSA senses physiological levels of H2O2 by iron-mediated histidine oxidation. Moreover, we show that PerRSA is poised to sense very low levels of endogenous H2O2, which normally cannot be sensed by B. subtilis PerRBS. This hypersensitivity of PerRSA accounts for the apparent lack of Fe(2+)-dependent repressor activity and consequent Mn(2+)-specific repressor activity under aerobic conditions. We also provide evidence that the activity of PerRSA is directly correlated with virulence, whereas it is inversely correlated with H2O2 resistance, suggesting that PerRSA may be an attractive target for the control of S. aureus pathogenesis.
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Ji
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Young-Bin
authors.initials: YB
authors.lastname: Won
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Yeh-Eun
authors.initials: YE
authors.lastname: Lee
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Tae-Woo
authors.initials: TW
authors.lastname: Choi
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Shin-Yeong
authors.initials: SY
authors.lastname: Ju
authors.affiliation: the Department of Biology, California State University Fresno, Fresno, California 93740-8034, and.
authors.forename: Hwan
authors.initials: H
authors.lastname: Youn
authors.affiliation: the Department of Microbiology, Cornell University, Ithaca, New York 14853-8101 jdh9@cornell.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Helmann
authors.affiliation: From the Department of Life Science and Research Center for Natural Sciences, Hanyang University, Seoul 133-791, Republic of Korea, jwl@hanyang.ac.kr.
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000332:Aerobiosis; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D015374:Biosensing Techniques; D005290:Ferric Compounds / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008670:Metals / Q000378:metabolism; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; D005290:Ferric Compounds; D008670:Metals; D006639:Histidine; D006861:Hydrogen Peroxide
keywords: Fur family; PerR; Staphylococcus aureus (S. aureus); histidine oxidation; hydrogen peroxide; metal homeostasis; oxidative stress; redox regulation