The disulfide bond isomerase DsbC is activated by an immunoglobulin-fold thiol oxidoreductase: crystal structure of the DsbC-DsbDalpha complex

Haebel, Peter

doi:10.1093/emboj/cdf489

Cited by 125 publications

(157 citation statements)

References 59 publications

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“…DsbD is composed of three domains: an N-terminal immunoglobulin-like domain (␣), a central hydrophobic core (␤) with eight transmembrane segments (TM segments), and a Cterminal periplasmic domain (␥), which appears to be a member of the thioredoxin superfamily (12)(13)(14)(15)(16)(17) (Fig. 1A).…”

mentioning

confidence: 99%

Role and location of the unusual redox-active cysteines in the hydrophobic domain of the transmembrane electron transporter DsbD

Katzen

Beckwith

2003

Proc. Natl. Acad. Sci. U.S.A.

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The central hydrophobic domain of the membrane protein DsbD catalyzes the transfer of electrons from the cytoplasm to the periplasm of Escherichia coli. Two cysteine residues embedded in transmembrane segments are essential for this process. Our results, based on cysteine alkylation and site-directed proteolysis, provide strong evidence that these residues are capable of forming an intramolecular disulfide bond. Also, by using a combination of two complementary genetic approaches, we show that both cysteines appear to be solvent-exposed to the cytoplasmic side of the inner membrane. These data are inconsistent with earlier topological models that place these residues on opposite sides of the membrane and permit the formulation of alternate hypotheses for the mechanism of this unusual transmembrane electron transfer.

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mentioning

confidence: 99%

Role and location of the unusual redox-active cysteines in the hydrophobic domain of the transmembrane electron transporter DsbD

Katzen

Beckwith

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…We found that 11/88 (12.5%) cases could be explained by such asymmetric multibinding. Figure 4b shows the 2:1 complex of the Escherichia coli disulphide bond isomerase with the N-terminal domain of the transmembrane electron transporter DsbD 42 . Here, a single DsbD chain is able to use two dissimilar surfaces to bind very similar regions containing the active site on each DsbC molecule.…”

Section: Resultsmentioning

confidence: 99%

“…Here, a single DsbD chain is able to use two dissimilar surfaces to bind very similar regions containing the active site on each DsbC molecule. It has been suggested that this asymmetric binding allows DsbD to distinguish oxidized from reduced DsbC 42 .…”

Section: Resultsmentioning

confidence: 99%

Structural and evolutionary versatility in protein complexes with uneven stoichiometry

et al. 2015

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Proteins assemble into complexes with diverse quaternary structures. Although most heteromeric complexes of known structure have even stoichiometry, a significant minority have uneven stoichiometry-that is, differing numbers of each subunit type. To adopt this uneven stoichiometry, sequence-identical subunits must be asymmetric with respect to each other, forming different interactions within the complex. Here we first investigate the occurrence of uneven stoichiometry, demonstrating that it is common in vitro and is likely to be common in vivo. Next, we elucidate the structural determinants of uneven stoichiometry, identifying six different mechanisms by which it can be achieved. Finally, we study the frequency of uneven stoichiometry across evolution, observing a significant enrichment in bacteria compared with eukaryotes. We show that this arises due to a general increased tendency for bacterial proteins to self-assemble and form homomeric interactions, even within the context of a heteromeric complex.

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“…28 However, Trx-fold proteins also undergo direct dithiol/disulfide exchange with other Trx-fold proteins. 29,30 Therefore, the interaction between two CXXC motifs at the amino termini of helices with the aid of the neighboring cis-proline as observed in RnQSOX1 may be relevant to other biological dithiol/disulfide exchange events.…”

Section: Discussionmentioning

confidence: 99%

“…The X-ray crystal structure model contained 498 amino acid residues in monomer A, 91 waters, and the cofactor FAD. Amino acid residues missing from the model (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(279)(280)(281)(282)(283)(284)(285)(286)(287)(288)(289)(290), and 548-550) were added using Discovery Studio 3.5 (Accelrys), prior to commencing simulations. Residues 25-36 and 548-550 were added in an extended conformation and subjected to geometry minimization and MD simulations, whereas the remainder of the enzyme was kept fixed.…”

Section: Model Construction For Simulationsmentioning

confidence: 99%

Enzyme structure captures four cysteines aligned for disulfide relay

et al. 2014

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Thioredoxin superfamily proteins introduce disulfide bonds into substrates, catalyze the removal of disulfides, and operate in electron relays. These functions rely on one or more dithiol/ disulfide exchange reactions. The flavoenzyme quiescin sulfhydryl oxidase (QSOX), a catalyst of disulfide bond formation with an interdomain electron transfer step in its catalytic cycle, provides a unique opportunity for exploring the structural environment of enzymatic dithiol/disulfide exchange. Wild-type Rattus norvegicus QSOX1 (RnQSOX1) was crystallized in a conformation that juxtaposes the two redox-active di-cysteine motifs in the enzyme, presenting the entire electron-transfer pathway and proton-transfer participants in their native configurations. As such a state cannot generally be enriched and stabilized for analysis, RnQSOX1 gives unprecedented insight into the functional group environments of the four cysteines involved in dithiol/disulfide exchange and provides the framework for analysis of the energetics of electron transfer in the presence of the bound flavin adenine dinucleotide cofactor. Hybrid quantum mechanics/molecular mechanics (QM/MM) free energy simulations based on the X-ray crystal structure suggest that formation of the interdomain disulfide intermediate is highly favorable and secures the flexible enzyme in a state from which further electron transfer via the flavin can occur.

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The disulfide bond isomerase DsbC is activated by an immunoglobulin-fold thiol oxidoreductase: crystal structure of the DsbC-DsbDalpha complex

Cited by 125 publications

References 59 publications

Role and location of the unusual redox-active cysteines in the hydrophobic domain of the transmembrane electron transporter DsbD

Role and location of the unusual redox-active cysteines in the hydrophobic domain of the transmembrane electron transporter DsbD

Structural and evolutionary versatility in protein complexes with uneven stoichiometry

Enzyme structure captures four cysteines aligned for disulfide relay

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