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Sulfoxide Reductase from Escherichia Coli Reveals a New GAF Domain Function

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Sulfoxide Reductase from Escherichia Coli Reveals a New GAF Domain Function Free methionine-(R)-sulfoxide reductase from Escherichia coli reveals a new GAF domain function Zhidong Lin*, Lynnette C. Johnson*, Herbert Weissbach†‡, Nathan Brot§, Mark O. Lively*, and W. Todd Lowther* *Center for Structural Biology, Department of Biochemistry, Wake Forest University School of Medicine, Winston–Salem, NC 27157; †Center for Molecular Biology and Biotechnology, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431; and §Hospital for Special Surgery, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021 Contributed by Herbert Weissbach, April 24, 2007 (sent for review March 7, 2007) The reduction of methionine sulfoxide (MetO) is mediated by recently revealed or proposed the existence of enzymes specific for methionine sulfoxide reductases (Msr). The MsrA and MsrB families free Met-(R)-O, free Met-(S)-O, peptide Met-(S)-O, and a mem- can reduce free MetO and MetO within a peptide or protein brane-associated protein(s), which is able to reduce all forms of context. This process is stereospecific with the S- and R-forms of MetO (7, 8, 10). The Msr with the highest specific activity in the E. MetO repaired by MsrA and MsrB, respectively. Cell extracts from coli MsrAϪBϪ soluble extract is the free Met-(R)-O reductase an MsrA؊B؊ knockout of Escherichia coli have several remaining (fRMsr). Nothing is currently known about the structure and Msr activities. This study has identified an enzyme specific for the catalytic mechanism of fRMsr. The specificity of the enzyme for free form of Met-(R)-O, fRMsr, through proteomic analysis. The free Met-(R)-O may have broad implications for resistance to recombinant enzyme exhibits the same substrate specificity and is oxidant stress. as active as MsrA family members. E. coli fRMsr is, however, 100- In this study, we have determined the identity of E. coli fRMsr to 1,000-fold more active than non-selenocysteine-containing through its purification from the MsrAϪBϪ strain and proteomic MsrB enzymes for free Met-(R)-O. The crystal structure of E. coli analysis. The recombinant enzyme has been expressed, purified, fRMsr was previously determined, but no known function was and characterized with regards to its substrate specificity, kinetic assigned. Thus, the function of this protein has now been deter- parameters, and ability to use the NADPH-thioredoxin (Trx) mined. The structural similarity of the E. coli and yeast proteins reductase (TrxR)-Trx reduction system. The fRMsr sequence is suggests that most fRMsrs use three cysteine residues for catalysis highly conserved across bacteria and yeast, but is not found in and the formation of a disulfide bond to enclose a small active site higher organisms, including humans. The fRMsr domain is part of cavity. This latter feature is most likely a key determinant of the large GAF domain family typified by cGMP-binding phos- substrate specificity. Moreover, E. coli fRMsr is the first GAF domain phodiesterases, Anabaena adenylyl cyclases, and the E. coli tran- family member to show enzymatic activity. Other GAF domain scription factor FhlA (11). These findings suggest that fRMsr proteins substitute the Cys residues and others to specifically bind represents a GAF domain with enzymatic activity, and that Met- cyclic nucleotides, chromophores, and many other ligands for (R)-O may function as a signaling molecule in response to oxidative signal potentiation. Therefore, Met-(R)-O may represent a signal- stress and nutrients. ing molecule in response to oxidative stress and nutrients via the TOR pathway in some organisms. Results Purification and Sequence Determination of E. coli fRMsr. Extracts of methionine oxidation ͉ methionine sulfoxide reductase the E. coli MsrAϪBϪ strain were used to identify the origins of the remaining Msr activity (7, 8). The extract was fractionated by eactive oxygen species cause cellular damage to lipids, DNA ammonium sulfate precipitation and a series of chromatographic Rand proteins. In proteins this damage includes the oxidation of columns. At each step of this process, the enzymatic activity for the methionine (Met) to methionine sulfoxide (MetO) (1). The addi- reduction of free MetO was measured by using the nitroprusside BIOCHEMISTRY tion of one oxygen atom to either lone pair of electrons of the sulfur assay. In this assay, Met reacts with the nitroprusside molecule, atom results in the formation of either the S-orR-form of MetO. leading to a change in absorbance at 540 nm (7, 8). Ammonium MetO has been implicated in a variety of disease states, and in some sulfate was found to inhibit the Msr activity, thus requiring dialysis instances the reduction or repair of this oxidation to Met restores of the samples before analysis. Only those fractions that exhibited the biological and enzymatic function of proteins (2). The reduction the highest specific activity were pooled at each step of the of MetO is mediated by several families of methionine sulfoxide purification. reductases (Msr). The structures and catalytic mechanisms of the The last stage of the fRMsr purification used a Resource Q MsrA and MsrB families have been extensively studied (3, 4). Key anion-exchange column. A comparison of the protein distribution features of both families are their strict substrate stereospecificity within the fractions by SDS/PAGE analysis with the Msr activity and ability to reduce both free MetO and MetO within a peptide profile revealed that only one group of protein bands showed or protein context. The MsrA and MsrB enzymes reduce Met-(S)-O correspondence. The putative fRMsr bands were excised and and Met-(R)-O, respectively. Moreover, these enzymes share a digested in-gel with trypsin. The resulting peptide fragments were reaction mechanism that involves the formation of a cysteine sulfenic acid intermediate (Cys-SOH) and the subsequent forma- tion and reduction of disulfide bonds which can differ depending on Author contributions: Z.L., H.W. and W.T.L. designed research; Z.L., L.C.J., H.W., and M.O.L. performed research; Z.L., H.W., N.B., and W.T.L. analyzed data; and Z.L. and W.T.L. wrote the number of Cys residues present. the paper. The Escherichia coli MsrB enzyme creates somewhat of a co- The authors declare no conflict of interest. nundrum. Crude extracts show little MsrB activity, and the recom- Abbreviations: fRMsr, free Met-(R)-O reductase; Met, methionine; MetO, methionine binant enzyme has significantly lower activity for free Met-(R)-O sulfoxide; MMTS, methyl methanethiosulfonate; Msr, methionine sulfoxide reductases; when compared with the MsrA enzymes (5). Thus, it is unclear how Trx, thioredoxin; TrxR, thioredoxin reductase. MsrB could enable an E. coli Met auxotroph to grow on Met-(R)-O ‡To whom correspondence should be addressed. E-mail: [email protected]. as a Met source (6). Additional Msr enzymes have been observed This article contains supporting information online at www.pnas.org/cgi/content/full/ Ϫ Ϫ which may explain these findings (6–9). Studies with the MsrA B 0703774104/DC1. strains of Escherichia coli and Saccharomyces cerevisiae have most © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0703774104 PNAS ͉ June 5, 2007 ͉ vol. 104 ͉ no. 23 ͉ 9597–9602 Downloaded by guest on September 27, 2021 blot analysis, using an anti-His tag antibody (Fig. 2B), confirmed that the 18-kDa fMsr does not contain the His-tag and begins with residue Met-19. The 24-kDa fMsr was found to contain the His-tag. Both species exhibited the same Msr activity with the nitroprusside assay and eluted at a higher molecular weight than expected on the gel filtration column. The 18-kDa species was analyzed by analytical ultracentrifugation at 0.3 mg mlϪ1 and found to have an apparent molecular weight of 36 kDa (data not shown). The addition of DTT Fig. 1. Sequence of E. coli fRMsr. Six tryptic fragments were identified by Ϫ Ϫ had no affect on the oligomeric state. At this time, it is not clear why mass spectrometry from E. coli fRMsr purified from MsrA B cells. The pep- tides are indicated in bold, underlined, and labeled 1–6. The identified the 18-kDa species was produced, although a weak ribosome sequence corresponds to the hypothetical E. coli protein NP࿝288269 and E. coli binding site sequence is present upstream of Met-19. Moreover, it yebR of unknown function. is not clear how the 18-kDa species was able to attach to the nickel NTA column, because it does not contain a His-tag. The 18-kDa fRMsr was used for the subsequent kinetic assays because of its high analyzed by reverse-phase HPLC coupled to the electrospray purity and abundance. interface of a Bruker (Newark, DE) Esquire HCT ion-trap mass spectrometer. The acquired peptide mass finger prints were queried Substrate Specificity and Kinetic Analysis of fRMsr. The reductase against a database of eubacteria proteins, using an in-house MAS- activity of E. coli MsrA and MsrB utilizes the reducing equivalents COT server. Six peptide matches with significant molecular weight from the Trx-TrxR-NADPH redox system (12, 13). MsrA and MsrB search scores were made to the hypothetical E. coli protein show stereospecificity toward their substrates and can reduce both NP࿝288269 (Fig. 1): (i) QPSDYIMNK (m/z, 548.3; charge, ϩ2); (ii) free MetO and peptide bound MetO, although the activity of MsrB TEFYADLNR (m/z, 564.2; charge, ϩ2); (iii) FTDEDEQGLR against free Met-(R)-O is much lower (3, 4, 14, 15). The reducing (m/z, 605.2; charge, ϩ 2); (iv) QLVAQLEK (m/z, 465.3; charge, system and substrate specificity of E. coli fRMsr were tested by ϩ2); (v) VLATTDYK (m/z, 456.2; charge, ϩ 2); (vi) FFASVAG measuring the reductase activity under a variety of assay conditions (m/z, 698.2; charge, ϩ1).
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