Broad Analysis of Vicinal Disulfides: Occurrences, Conformations with Cis or with Trans Peptides, and Functional Roles Including Sugar Binding

Richardson, Jane S.; Videau, Lizbeth L.; Williams, Christopher J.; Richardson, David C.

doi:10.1016/j.jmb.2017.03.017

Cited by 34 publications

(42 citation statements)

References 75 publications

(96 reference statements)

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“…Strikingly, this groove is flanked on both sides by Cys pairs. Although closely spaced cysteines often bind metal prosthetic groups, adjacent cysteines are unusual, and where they do occur they rarely bind the same metal ligand (Miller et al, 1989;Richardson et al, 2017). Furthermore, adjacent cysteines are not known to bind [Fe-S] clusters (Roche et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

PSA3, a Protein on the Stromal Face of the Thylakoid Membrane, Promotes Photosystem I Accumulation in Cooperation with the Assembly Factor PYG7

2017

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PSI is a large protein-pigment complex located in the thylakoid membrane in cyanobacteria, plants, and algae. Although the structure and components of PSI are well characterized, mechanisms that orchestrate its assembly are poorly understood. In this study, we discovered a novel nucleus-encoded protein, Photosystem I Assembly3 (PSA3), that is required for PSI accumulation. PSA3 is conserved among green photosynthetic eukaryotes but is lacking in cyanobacteria. Mutations in the psa3 gene cause the specific loss of PSI in Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). Ribosome profiling and pulse-labeling analyses showed that chloroplast-encoded PSI subunits are synthesized at normal rates in psa3 mutants, indicating that PSA3 is involved in the biogenesis of PSI at a posttranslational step. PSA3 resides on the stromal face of the thylakoid membrane, where it is found in a complex that is slightly smaller than PSI. Structural predictions suggest that PSA3 binds a basic peptide in a manner that is sensitive to the oxidation state of Cys pairs flanking the predicted peptide binding groove. PSA3 and the previously described PSI biogenesis factor PYG7 interact in yeast two-hybrid and bimolecular fluorescence complementation assays, and they are found in thylakoid membrane complexes of similar size. These and other results indicate that PSA3 cooperates with PYG7 to promote the stable assembly of PSI, and that the PsaC subunit is likely to be the primary target of their action.

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Section: Discussionmentioning

confidence: 99%

PSA3, a Protein on the Stromal Face of the Thylakoid Membrane, Promotes Photosystem I Accumulation in Cooperation with the Assembly Factor PYG7

2017

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“…Examination of individual examples was done in the KiNG display and modeling program (Chen 2009), using 2mFo-DFc electron density maps and sometimes difference-density maps, plus model-validation markup from MolProbity Williams 2017); in most cases the literature references were also consulted. All figures except Figure 4 were produced in KiNG.…”

Section: Methodsmentioning

confidence: 99%

“…The trans conformation is also possible, and actually more frequent, for vicinal disulfides. Therefore we have analyzed the occurrence patterns, the possible conformations (2 for cis and 2 for trans), and the varied functional roles of vicinal SS in a separate paper (Richardson 2017). They can bind ligands (usually the undecorated side of a ring, as in Fig.…”

Section: Cys-cis-cys: Vicinal Disulfidesmentioning

confidence: 99%

Cis-nonPro Peptides: Genuine Occurrences and their Functional Roles

Williams¹,

Ll²,

Dc³

et al. 2018

Preprint

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Cis-nonPro peptides, a very rare feature in protein structures, are of considerable importance for two opposite reasons. On one hand, their genuine occurrences are mostly found at sites critical to biological function, from the active sites of carbohydrate enzymes to rare adjacent-residue disulfide bonds. On the other hand, a cis-nonPro can easily be misfit into weak or ambiguous electron density, which has led to a high incidence of unjustified cis-nonPro over the last decade. This paper uses the greatly expanded crystallographic data and newly stringent quality-filtering to identify the genuine occurrences and survey both individual examples and broad patterns of their functionality. The accompanying paper describes the problem of cis-nonPro over-use, including its causes, validation, and correction.We explain the procedure developed to identify genuine cis-nonPro examples with almost no false positives, including the new observation that peptides with a glycine on one side or the other need extra care to avoid mis-assignment as cis-nonPro. We then survey a sample of the varied functional roles and structural contexts of cis-nonPro, emphasizing aspects not previously covered systematically: the preferred occurrence at b-strand ends in TIM barrel structures, the concentration of occurrence in proteins that process, bind, or contain carbohydrates, and the resulting complications in defining a simple occurrence frequency.

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“…This in turn suggests two possible pathways for kinetic folding of this ICK peptide: one in which a vicinal disulfide bond initially forms between [Cys(III)-Cys(IV)] and one where the first bond forms between [Cys(V)-Cys(VI)]. Vicinal disulfide bonds are unusual among stably-folded proteins as they impose tight conformational restrictions on the peptide backbone immediately surrounding the disulfide (Richardson et al, 2017). However, they have been described before in previous naturally-occurring peptides (Wang et al, 2000; de FIGURE 3 | Normalized base peak intensity (BPI) chromatogram determined by LC-MS/MS for the products of folding linear ProTx-II 2 in water after 7 days.…”

Section: Analysis Of Oxidative Folding Pathways Of the Native Protx-imentioning

confidence: 99%

A Chemical Biology Approach to Probing the Folding Pathways of the Inhibitory Cystine Knot (ICK) Peptide ProTx-II

McCarthy¹,

Robinson²,

Thalassinos

et al. 2020

Front. Chem.

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Peptide toxins that adopt the inhibitory cystine knot (ICK) scaffold have very stable three-dimensional structures as a result of the conformational constraints imposed by the configuration of the three disulfide bonds that are the hallmark of this fold. Understanding the oxidative folding pathways of these complex peptides, many of which are important therapeutic leads, is important in order to devise reliable synthetic routes to correctly folded, biologically active peptides. Previous research on the ICK peptide ProTx-II has shown that in the absence of an equilibrating redox buffer, misfolded intermediates form that prevent the formation of the native disulfide bond configuration. In this paper, we used tandem mass spectrometry to examine these misfolded peptides, and identified two non-native singly bridged peptides, one with a Cys(III)-Cys(IV) linkage and one with a Cys(V)-Cys(VI) linkage. Based on these results, we propose that the C-terminus of ProTx-II has an important role in initiating the folding of this peptide. To test this hypothesis, we have also studied the folding pathways of analogs of ProTx-II containing the disulfide-bond directing group penicillamine (Pen) under the same conditions. We find that placing Pen residues at the C-terminus of the ProTx-II analogs directs the folding pathway away from the singly bridged misfolded intermediates that represent a kinetic trap for the native sequence, and allows a fully oxidized final product to be formed with three disulfide bridges. However, multiple two-disulfide peptides were also produced, indicating that further study is required to fully control the folding pathways of this modified scaffold.

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Broad Analysis of Vicinal Disulfides: Occurrences, Conformations with Cis or with Trans Peptides, and Functional Roles Including Sugar Binding

Cited by 34 publications

References 75 publications

PSA3, a Protein on the Stromal Face of the Thylakoid Membrane, Promotes Photosystem I Accumulation in Cooperation with the Assembly Factor PYG7

PSA3, a Protein on the Stromal Face of the Thylakoid Membrane, Promotes Photosystem I Accumulation in Cooperation with the Assembly Factor PYG7

Cis-nonPro Peptides: Genuine Occurrences and their Functional Roles

A Chemical Biology Approach to Probing the Folding Pathways of the Inhibitory Cystine Knot (ICK) Peptide ProTx-II

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