Vicinal disulfide bridge conformers by experimental methods and by ab initio and DFT molecular computations

Hudáky, Ilona; Gáspári, Zoltán; Carugo, Oliviero; Cemazar, Masa; Pongor, Sándor; Perczel, András

doi:10.1002/prot.10581

Cited by 30 publications

(46 citation statements)

References 59 publications

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“…Previous conformational analysis of oxidized CC rings in peptides has suggested conformations with a cis-amide (11,29). In contrast, analysis of CC motifs in the PDB concluded that the occurrence of the cis conformation was remarkably low (30). Hence, although the cis structures have 77 Se chemical shifts in the region of interest, they may not have contributed to the observed spectra.…”

Section: Density Functional Theory Conformation Search and Gauge-invamentioning

confidence: 88%

Redox active motifs in selenoproteins

Lutz

Pepelyayeva

et al. 2014

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

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Selenoproteins use the rare amino acid selenocysteine (Sec) to act as the first line of defense against oxidants, which are linked to aging, cancer, and neurodegenerative diseases. Many selenoproteins are oxidoreductases in which the reactive Sec is connected to a neighboring Cys and able to form a ring. These Sec-containing redox motifs govern much of the reactivity of selenoproteins. To study their fundamental properties, we have used 77 Se NMR spectroscopy in concert with theoretical calculations to determine the conformational preferences and mobility of representative motifs. This use of 77 Se as a probe enables the direct recording of the properties of Sec as its environment is systematically changed. We find that all motifs have several ring conformations in their oxidized state. These ring structures are most likely stabilized by weak, nonbonding interactions between the selenium and the amide carbon. To examine how the presence of selenium and ring geometric strain governs the motifs' reactivity, we measured the redox potentials of Sec-containing motifs and their corresponding Cys-only variants. The comparisons reveal that for C-terminal motifs the redox potentials increased between 20-25 mV when the selenenylsulfide bond was changed to a disulfide bond. Changes of similar magnitude arose when we varied ring size or the motifs' flanking residues. This suggests that the presence of Sec is not tied to unusually low redox potentials. The unique roles of selenoproteins in human health and their chemical reactivities may therefore not necessarily be explained by lower redox potentials, as has often been claimed.

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Section: Density Functional Theory Conformation Search and Gauge-invamentioning

confidence: 88%

Redox active motifs in selenoproteins

Lutz

Pepelyayeva

et al. 2014

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

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“…The cis and trans isomers of a model peptide of the form CH 3 CO-[CysCys]-NH 2 with the S-S disulfide torsional angles of Ϯ90 were constructed using the GausView molecule building tools. The geometric parameters for these starting structures were derived from the lowest energy conformers from previous ab initio calculations on a similar model peptide (21). Energy minimizations were performed on the four starting structures of the model peptide.…”

Section: Methodsmentioning

confidence: 99%

“…Instead, many workers have speculated on a role in receptor gating involving cis-trans isomerization of the amide and/or gauche(ϩ)/gauche(Ϫ) interconversion of the disulfide (10,18,19,21,22). Conventional mutagenesis studies are expected to produce severely impaired receptors, and so it has been challenging to design unambiguous probes of disulfide function.…”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

Blum

Gleitsman

Lester

et al. 2011

Journal of Biological Chemistry

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The defining feature of the ␣ subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains uncertain. Using mutant cycle analysis and unnatural residue mutagenesis, including backbone mutagenesis of the peptide bond of the vicinal disulfide, we have established the presence of a network of hydrogen bonds that extends from that peptide NH, across a ␤ turn to another backbone hydrogen bond, and then across the subunit interface to the side chain of a functionally important Asp residue in the non-␣ subunit. We propose that the role of the vicinal disulfide is to distort the ␤ turn and thereby properly position a backbone NH for intersubunit hydrogen bonding to the key Asp.

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“…[42][43][44] The disulfide bond between two adjacent cysteine residues (i.e., a vicinal disulfide bond) is referred to in the literature as a "forbidden" disulfide, involving an eightmembered ring structure in which the peptide bond typically adopts a highly distorted, non-planar trans conformation. [43][44][45][46] Vicinal disulfides have been reported, for example, in insecticidal atracotoxins, 47 the Helicobacter pylori heat shock protein A 48 and the human replication protein A (RPA). 49 The formation of a vicinal disulfide bond in RPA alters the direction of the backbone and causes a strain in the peptide chain.…”

Section: Discussionmentioning

confidence: 99%

“…The peptide bond in the eight-memberd ring of the vicinal Cys29-Cys30 adopts a clearly distorted trans-conformation (w 5 103.28), consistent with the other reported vicinal disulfide bonds. 45,46 Therefore, the zinc center in SAP30L forms a redox switch, which, upon oxidative stress, releases the coordinated zinc ion with a concomitant formation of the two specific disulfide bonds, a vicinal Cys29-Cys30 and Cys38-Cys74 (Fig. 6).…”

Section: Discussionmentioning

confidence: 99%

Redox‐dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function

et al. 2015

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Sin3A-associated protein 30-like (SAP30L) is one of the key proteins in a multi-subunit protein complex involved in transcriptional regulation via histone deacetylation. SAP30L, together with a highly homologous SAP30 as well as other SAP proteins (i.e., SAP25, SAP45, SAP130, and SAP180), is an essential component of the Sin3A corepressor complex, although its actual role has remained elusive. SAP30L is thought to function as an important stabilizing and bridging molecule in the complex and to mediate its interactions with other corepressors. SAP30L has been previously shown to contain an N-terminal Cys 3 His type zinc finger (ZnF) motif, which is responsible for the key protein-protein, protein-DNA, and protein-lipid interactions. By using high-resolution mass spectrometry, we studied a redox-dependent disulfide bond formation in SAP30L ZnF as a regulatory mechanism for its structure and function. We showed that upon oxidative stress SAP30L undergoes the formation of two specific disulfide bonds, a vicinal Cys29-Cys30 and Cys38-Cys74, with a concomitant release of the coordinated zinc ion. The oxidized protein was shown to remain folded in solution and to bind signaling phospholipids. We also determined a solution NMR structure for SAP30L ZnF that showed an overall fold similar to that of SAP30, determined earlier. The NMR titration experiments with lipids and DNA showed that the binding is mediated by the C-terminal tail as well as both a-helices of SAP30L ZnF. The implications of these results for the structure and function of SAP30L are discussed.

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Vicinal disulfide bridge conformers by experimental methods and by ab initio and DFT molecular computations

Cited by 30 publications

References 59 publications

Redox active motifs in selenoproteins

Redox active motifs in selenoproteins

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

Redox‐dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function

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