RsrA, an anti-sigma factor regulated by redox change

Kang, Joo-Seong

doi:10.1093/emboj/18.15.4292

Cited by 228 publications

(305 citation statements)

References 25 publications

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“…The sensor regions present in Hsp33 have individual uses in other redox-regulated proteins (for example, RsrA) or temperature-regulated chaperones (for example, GrpE and Hsp26) [27][28][29] . In contrast to Hsp33, however, these proteins are regulated by only a single stress signal and therefore require only a single stress sensor.…”

Section: Discussionmentioning

confidence: 99%

The redox-switch domain of Hsp33 functions as dual stress sensor

Ilbert

Horst

Ahrens

et al. 2007

Nat Struct Mol Biol

167

205

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The redox-regulated chaperone Hsp33 is specifically activated upon exposure of cells to peroxide stress at elevated temperatures. Here we show that Hsp33 harbors two interdependent stress-sensing regions located in the C-terminal redox-switch domain of Hsp33: a zinc center sensing peroxide stress conditions and an adjacent linker region responding to unfolding conditions. Neither of these sensors works sufficiently in the absence of the other, making the simultaneous presence of both stress conditions a necessary requirement for Hsp33's full activation. Upon activation, Hsp33's redox-switch domain adopts a natively unfolded conformation, thereby exposing hydrophobic surfaces in its N-terminal substrate-binding domain. The specific activation of Hsp33 by the oxidative unfolding of its redox-switch domain makes this chaperone optimally suited to quickly respond to oxidative stress conditions that lead to protein unfolding.Reactive oxygen species develop as unavoidable consequences of aerobic life. Their oxidizing effects on most cellular macromolecules can be deleterious to cells and organisms 1 . Cells have developed effective antioxidant systems to counteract this hazard (for review, see ref. 2 ). Disruption of the fine balance between oxidants and antioxidants, however, leads to the accumulation of reactive oxygen species and to a condition termed oxidative stress 3 . Oxidative stress conditions have been shown to develop in, and may even cause, numerous physiological and pathological conditions, such as aging, heart disease, diabetes and neurodegenerative diseases 4 .

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Section: Discussionmentioning

confidence: 99%

The redox-switch domain of Hsp33 functions as dual stress sensor

Ilbert

Horst

Ahrens

et al. 2007

Nat Struct Mol Biol

167

205

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“…Upon exposure to oxidative stress, disulfide bonds of RsrA form, and zinc is released. This is accompanied by major structural rearrangements that lead to the release of R , which is then able to activate transcription of its target genes (18,30). In contrast to Hsp33 where the oxidized conformation unfolds and the reduced zinc-bound conformation is fully structured, disulfidebonded RsrA appears to contain more ␣-helical secondary structure than the reduced, zinc-bound form.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Redox-regulated Chaperone Hsp33 by Domain Unfolding

Graf

Martinez-Yamout

VanHaerents

et al. 2004

Journal of Biological Chemistry

110

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The molecular chaperone Hsp33 in Escherichia coli responds to oxidative stress conditions with the rapid activation of its chaperone function. On its activation pathway, Hsp33 progresses through three major conformations, starting as a reduced, zinc-bound inactive monomer, proceeding through an oxidized zinc-free monomer, and ending as a fully active oxidized dimer. While it is known that Hsp33 senses oxidative stress through its C-terminal four-cysteine zinc center, the nature of the conformational changes in Hsp33 that must take place to accommodate this activation process is largely unknown. To investigate these conformational rearrangements, we constructed constitutively monomeric Hsp33 variants as well as fragments consisting of the redox regulatory C-terminal domain of Hsp33. These proteins were studied by a combination of biochemical and NMR spectroscopic techniques. We found that in the reduced, monomeric conformation, zinc binding stabilizes the C terminus of Hsp33 in a highly compact, ␣-helical structure. This appears to conceal both the substrate-binding site as well as the dimerization interface. Zinc release without formation of the two native disulfide bonds causes the partial unfolding of the C terminus of Hsp33. This is sufficient to unmask the substrate-binding site, but not the dimerization interface, rendering reduced zinc-free Hsp33 partially active yet monomeric. Critical for the dimerization is disulfide bond formation, which causes the further unfolding of the C terminus of Hsp3 and allows the association of two oxidized Hsp33 monomers. This then leads to the formation of active Hsp33 dimers, which are capable of protecting cells against the severe consequences of oxidative heat stress.

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“…In fact, many bacteria-including Bacillus, Mycobacteria, Rhodobacter, and Streptomyces-do not include glutaredoxins or thioredoxins in their H 2 O 2 -inducible regulons (123)(124)(125). Instead, for example, Streptomyces controls synthesis of its thioredoxins with an anti-sigma factor protein that is activated when sulfur exchange reactions create a disulfide bond (126); notably, this system is easily triggered by diamide but requires millimolar doses of H 2 O 2 . Thus at the moment the importance of thiol oxidation in H 2 O 2 toxicity, and the role that redoxins play in H 2 O 2 defenses, remain puzzling questions.…”

Section: 52mentioning

confidence: 99%

Cellular Defenses against Superoxide and Hydrogen Peroxide

Imlay

2008

Annu. Rev. Biochem.

1,282

1,276

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Life evolved in an anaerobic world; therefore, fundamental enzymatic mechanisms and biochemical pathways were refined and integrated into metabolism in the absence of any selective pressure to avoid reactivity with oxygen. After photosystem 2 appeared, environmental oxygen levels rose very slowly. During this time microorganisms acquired oxygen tolerance by jettisoning enzymes that use glycyl radicals and low-potential iron-sulfur clusters, which can be directly poisoned by oxygen. They also developed mechanisms to defend themselves against O 2 − and hydrogen peroxide, partially reduced oxygen species that are generated as inadvertent by-products of aerobic metabolism. These species are more chemically reactive than is molecular oxygen itself. Contemporary organisms have inherited both the vulnerabilities and the defenses of these ancestral microbes. Current research seeks to identify these, and bacteria comprise an exceptionally accessible experimental system that has provided the many of the answers. This manuscript reviews recent developments and identifies remaining puzzles.

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RsrA, an anti-sigma factor regulated by redox change

Cited by 228 publications

References 25 publications

The redox-switch domain of Hsp33 functions as dual stress sensor

The redox-switch domain of Hsp33 functions as dual stress sensor

Activation of the Redox-regulated Chaperone Hsp33 by Domain Unfolding

Cellular Defenses against Superoxide and Hydrogen Peroxide

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