Redox control of secondary structure in a designed peptide

Dado, Gregory P.; Gellman, Samuel H.

doi:10.1021/ja00079a060

Cited by 118 publications

(94 citation statements)

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“…These results are qualitatively in good agreement with experiments which show that polyalanine adopts an α-helical conformation in hydrophobic environments such as the solid state or in non-polar organic solutions and a β-structure conformation in polar aqueous solution 88,[106][107][108][109][110][111] . This is similarly observed in experiments on many heterogeneous peptides which can be folded into alternative stable structures by changing the solution conditions such as the pH, salt or organic cosolvent concentration, peptide concentration, and the redox state [112][113][114][115][116][117][118][119][120][121][122][123][124][125][126] . Interestingly, Knott and Chan 95 recently investigated the impact of the relative strengths of the hydrophobic and hydrogen bonding interaction on folding of polypeptide chains using a similar intermediate-resolution protein model 94 but with a continuous potential.…”

Section: Resultsmentioning

confidence: 80%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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Fibrillary protein aggregates rich in β-sheet structure have been implicated in the pathology of several neurodegenerative diseases. In this work, we investigate the formation of fibrils by performing discontinuous molecular dynamics simulations on systems containing 12 to 96 model Ac-KA 14 K-NH 2 peptides using our newly-developed off-lattice, implicit-solvent, intermediateresolution model, PRIME. We find that at a low concentration, random-coil peptides assemble into α-helices at low temperatures. At intermediate concentrations, random-coil peptides assemble into α-helices at low temperatures and large β-sheet structures at high temperatures. At high concentrations, the system forms β-sheets over a wide range of temperatures. These assemble into fibrils above a critical temperature which decreases with concentration and exceeds the isolated peptide's folding temperature. At very high temperatures and all concentrations, the system is in a random-coil state. All of these results are in good qualitative agreement with those by Blondelle and coworkers on Ac-KA 14 K-NH 2 peptides. The fibrils observed in our simulations mimic the structural characteristics observed in experiments in terms of the number of sheets formed, the values of the intra-and inter-sheet separations, and the parallel peptide arrangement within each β-sheet. Finally, we find that when the strength of the hydrophobic interaction between non-polar sidechains is high compared to the strength of hydrogen bonding, amorphous aggregates, rather than fibrillar aggregates, are formed.

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Section: Resultsmentioning

confidence: 80%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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“…Similarly, Nle exhibits an even higher intrinsic preference for ␣-helical states, but lower preferences for ␤-sheet conformations than Met residues (52). In the absence of experimental data on structural propensities of Mox residues, which conceivably could prefer ␤-sheet over ␣-helical conformation because of their hydrophilicity, we have addressed this question with the suitable model peptide YLKAMLEAMAKLMAKLMA-NH 2 of Dado and Gellman (17), which showed an ␣3␤ transition on Metoxidation. The Nle-peptide exhibits the typical ␣-helical CD profile with a very high content of ordered structure (Ͼ80% ␣-helix).…”

Section: Oxidation Of Met Residues In Rhprp C and ␣3␤ Structural Convmentioning

confidence: 99%

“…1 A). Indeed, this redox-controlled Met7Met(O) reaction can induce an ␣-helix7␤-sheet conformational switch in model peptides (17). Although Met is a rare amino acid in proteins (18), there are many important proteins whose activity is altered by Met-oxidation such as 1-antitrypsin calmodulin, fibronectin, cytochrome C, apolipoprotein, chymotrypsin, hemoglobin, etc.…”

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confidence: 99%

Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein

Wolschner

Giese

Kretzschmar

et al. 2009

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

104

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Prion disease is characterized by the ␣3␤ structural conversion of the cellular prion protein (PrP C ) into the misfolded and aggregated ''scrapie'' (PrP Sc ) isoform. It has been speculated that methionine (Met) oxidation in PrP C may have a special role in this process, but has not been detailed and assigned individually to the 9 Met residues of full-length, recombinant human PrP C [rhPrP C (23-231)]. To better understand this oxidative event in PrP aggregation, the extent of periodate-induced Met oxidation was monitored by electrospray ionization-MS and correlated with aggregation propensity. Also, the Met residues were replaced with isosteric and chemically stable, nonoxidizable analogs, i.e., with the more hydrophobic norleucine (Nle) and the highly hydrophilic methoxinine (Mox). The Nle-rhPrP C variant is an ␣-helix rich protein (like MetrhPrP C ) resistant to oxidation that lacks the in vitro aggregation properties of the parent protein. Conversely, the Mox-rhPrP C variant is a ␤-sheet rich protein that features strong proaggregation behavior. In contrast to the parent Met-rhPrP C , the Nle/Moxcontaining variants are not sensitive to periodate-induced in vitro aggregation. The experimental results fully support a direct correlation of the ␣3␤ secondary structure conversion in rhPrP C with the conformational preferences of Met/Nle/Mox residues. Accordingly, sporadic prion and other neurodegenerative diseases, as well as various aging processes, might also be caused by oxidative stress leading to Met oxidation.conformational switch ͉ expanded genetic code ͉ methionine sulfoxide reductase ͉ noncanonical analogs ͉ unnatural amino acid sequence

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“…Rapid induction of defined secondary structural elements can arise from constraining conformational search space (21) and by increasing the concentration of the potential hydrophobic interactive surfaces (22). Therefore, it is conceivable that the folding pathways for unstructured polypeptides can be influenced by interaction with the hydrophobic peptide binding surface of the chaperonins (8,9).…”

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confidence: 99%

Interactions between the GroE Chaperonins and Rhodanese

Smith

Fisher

1995

Journal of Biological Chemistry

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Efficient renaturation of urea-denatured rhodanese using the chaperonin GroE system requires GroEL, GroES, and ATP. At high concentrations this renaturation also requires the substrate thiosulfate to have been present during GroEL-rhodanese complex formation. When thiosulfate is present the GroEL-rhodanese complex can be concentrated to greater than 1 mg/ml rhodanese with little effect on the efficiency of renaturation. However, if complex is formed in the absence of thiosulfate, renaturation of rhodanese in the presence of thiosulfate shows a critical concentration of approximately 0.4 mg/ml, above which renaturation yields drop dramatically. This critical concentration appears to be related to an aggregation event in the refolding of rhodanese. The nucleotide free or ADP-bound form of GroEL also binds to rhodanese that has been either already renatured or never denatured. The bound rhodanese has no activity but can be released from GroEL with ATP recovering 90% of control activity. The data presented herein support a release and rebinding mechanism for the GroE-assisted refolding of rhodanese. It also suggests GroEL binds several protein folding intermediates along the entire refolding pathway.In vivo, molecular chaperones such as hsp70/hsp40 and the chaperonins prevent the accumulation of inappropriate protein aggregates and enhance the acquisition of native protein structure. For instance in Escherichia coli, chaperonins are known to bind to a host of partially folded proteins (1, 2) and act in concert with the upstream (hsp70/40) molecular chaperones (3, 4) to prevent misfolding and aggregation. While the mechanism through which this is accomplished has been the subject of intense research, it is still unclear exactly how chaperones assist protein folding.The most thoroughly studied chaperonin system is the GroE proteins (GroEL and GroES) isolated from E. coli. Results from in vitro protein folding experiments indicate that the GroE chaperonins inhibit protein misfolding and aggregation (5-7). Two models have been proposed to explain this observation. The first model suggests that the GroE system sequesters the folding protein inside a cavity of the GroEL chaperonin and allows the protein to fold in a shielded environment through repeated ATP-dependent release and rebinding reactions (7, 10, 11). The second model suggests that the protein is released from GroEL and folds free in solution but will rebind to the chaperonin if it is not committed to fold to the native state. In this latter model, protein aggregation is prevented by decreasing the concentration of free, aggregation-prone, folding intermediates.

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Redox control of secondary structure in a designed peptide

Cited by 118 publications

References 0 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein

Interactions between the GroE Chaperonins and Rhodanese

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