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An Atlas of Interpersonal Situations. An Atlas of Gross Pathology. An atlas of gynecologic oncology. An Atlas of Irish History. An Atlas of Atopic Eczema. An Atlas of Erectile Dysfunction. Recommend Documents. Keith B. Oldham Trent Baldwin and Jon Birtwistle University of S In nearly all Trx fold mechanisms that involve the reduction of a substrate, the first step is a nucleophilic attack by a thiolate from the CxxC motif, typically from the N-terminal cysteine, eventually leading to an oxidized active site that is reduced through a variety of mechanisms to regenerate the active enzyme.

In Figures 5 — 8 , these different active site types are mapped onto the sequence network of the Trx fold class, with Figures 5 — 7 including group-wise depictions of the types of amino acids found at the two key positions of the CxxC motif. These data show that the most common substitution at a CxxC position is cysteine-to-serine or cysteine-to-threonine, depending on the superfamily. Most of the sequences in Fig. Just 8. The same sequence similarity network from Fig. CxxxC means that the two cysteines are present and separated by three amino acids. Examples of each type are shown in Fig.

Large nodes represent sequences that are associated with the structures from Fig. Cysteines and selenocysteines are treated as equivalent in this figure. Letter labels in blue correspond to sequence groups in Figures 5 — 7. Most alternative variations of the CxxC active site motif are typified by a specific Trx fold superfamily or subclass. Characterization of the mechanisms in model proteins has been the focus of a great deal of investigation, and the presence of many exceptions to the expected motifs, particularly in classes that contain well-characterized proteins, are surprising and expand on the observations by Fomenko and Gladyshev in model organisms [16] , [17].

The Cxxc motif is traditionally associated with the monothiol glutaredoxins Fig. Other groups falling into the Cxxc category are the glutathione peroxidases Fig. The most common example of the cxxC motif, in which the C-terminal Cys provides the nucleophilic thiolate, is the peroxiredoxins Fig. In most Prx-like proteins, this nucleophile is likely stabilized in part by an N-terminal threonine Only the SCO1-type proteins exhibit a dithiol motif with two cysteines separated by three residues Fig. In addition to their structural distinctiveness relative to other members of the Trx fold Fig.

The GST kappa class Fig. Many cytosolic GSTs are associated with a similar catalytic serine [57] Fig. However, the relatively recently characterized omega GSTs Fig. GST superfamily member yfcG from E. The primarily eukaryotic GST class Fig. Thus, from the perspective of structure and catalysis, GSTs are truly a unique constituent of the Trx fold class.

One of the next challenges for understanding how function is delivered in the Trx fold class will be to show how the structurally distant GSTs retain and modify aspects of the Trx fold to enable their unique spectrum of catalytic and in vivo function. In , Copley and colleagues postulated that peroxiredoxins evolved from a thioredoxin-like ancestor, noting that peroxiredoxins and thioredoxins could be related by sequence and structure using bridging motifs found in the cytochrome maturation proteins CMP [58].

These transitive relationships are also seen in the analysis in this work, both from the perspective of sequence and from structure. In terms of sequence similarity, there is a tighter bridge between thioredoxins and CMPs, whereas considering primarily structural information, the relationship between CMPs and peroxiredoxins is closer. Although a large-scale analysis does not provide mechanistic details, incorporating information from the full fold class rather than tracking isolated examples reinforces and contextualizes the significance of the relationship.

There is an unambiguous sequence relationship between the CMPs and thioredoxins. As shown in Fig. The sequence similarity network in Fig. The biophysical function of the cis -proline is not well-defined; it likely forms part of the binding site for substrate polypeptides [58] and may serve to prevent metal binding to the CxxC motif [59]. In peroxiredoxins, the cis -proline position is occupied by an arginine. Unsurprisingly, the arginine plays a different role: the positively charged side chain is near enough to help lower the pK a of the peroxidatic cysteine, presumably enhancing its nucleophilicity [60].

A Subset of the sequence similarity network from Fig. The orange path traces transitive sequence similarity relationships between human Trx 2, passing through B.

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B The same path—connecting the structures associated with the sequences in A—traced through a subset of the structure-based network from Fig. C The same path traced through a subset of the structure-based hierarchical clustering of representative structures from Fig. There is clear structural similarity between peroxiredoxins and thioredoxins, with a representative CMP structure PDB:1KNG occupying an intermediate position between the other two classes, while being slightly more similar to the peroxiredoxins Fig. This structural similarity is greater than simply sharing variants of the thioredoxin fold: both the CMPs and the peroxiredoxins have an N-terminal extension and an additional insertion between the second beta strand and second alpha helix of the Trx fold discussed in Results I.

Furthermore, the glutathione peroxidases are also structurally intermediate between the peroxiredoxin and thioredoxin groups Fig. Thus peroxiredoxins, glutathione peroxidases, and CMPs are more similar to one another with respect to overall structural similarity and presence of secondary structure elements when compared to thioredoxin. These bridging motifs present in sequence and structure bolster the relationship between thioredoxins and peroxiredoxins, and provide examples of how modifications to the Trx fold correlate with changes in function.

By viewing the peroxiredoxin-thioredoxin relationship from within the context of the entire Trx fold class, we note two new points of interest: First, that it is important to consider glutathione peroxidases as an additional bridging group. From a functional perspective, glutathione peroxidases are a special class of peroxiredoxin; they are structurally more similar to CMPs than other peroxiredoxin classes, and they are also intermediate in structure between the thioredoxins and other peroxiredoxin classes.

The Trx fold class is one of the largest sets of proteins likely to have evolved from a common ancestor, incorporating at least eighteen individual superfamilies and comprising about 0. In this work, we have shown how each protein in the fold class can be viewed from within the context of the features provided by the Trx fold, alongside each other member of the class.

What this brings is a new emphasis: here, proteins were compared to the entire population of their class, rather than just to a few well-known archetypal examples. By observing population trends, a new picture has emerged that incorporates more of the real complexity present in the thioredoxin fold class—for example, almost no sequence motif is conserved absolutely—and there is additional information from considering natural groupings of similar proteins rather than reducing protein-protein similarity to closest neighbors.

Viewing features of the glutaredoxin-like proteins demonstrates how unusual they are relative to the other major superfamilies: glutaredoxin domains are quite diverse and are found embedded in sequences of dramatically varying lengths and in combination with other domains, indicating an enhanced level of modularity relative to other Trx fold domains.

Similarly, glutathione transferases are revealed as especially unique when viewed from the context of the entire Trx fold. While the Trx fold class as a whole is dominated by bacterial sequences, a few groups like protein disulfide isomerases were uniquely present in eukaryotic organisms.

Finally, as demonstrated with the cytochrome maturation proteins, the Trx fold context can be used to show how features of one superfamily are either retained or modified in a neighboring superfamily, tracing out a transitive similarity pathway. The Trx fold class is primarily composed of proteins that have no annotated function and have never been investigated in vitro.

However, identifying where a protein falls within the similarity landscapes described here provides information about basic catalytic capabilities of that protein. Boundaries between functional classes are implicit in the network topologies, and this can inform the characterization of proteins without annotations, as well as expose proteins that may have been misannotated. This analysis provides a working blueprint for predicting the catalytic possibilities of new members of the Trx fold class.

To assemble all sequences from the Trx fold class, the data set consisted of the union of all sequences that were members of the PFAM Thioredoxin-like Clan [28] and all sequences classified into relevant Trx fold superfamilies in SwissProt [9].

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This union set of all Trx fold sequences contained 29, sequences. Additionally, only sequences longer than 60 amino acids were used in the networks, resulting in a data set of 4, sequences.

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The sequence similarity networks were constructed as described in Atkinson et al. The structure similarity networks were constructed and visualized in the same way, except pairwise similarity between structure chains was determined using FAST [64]. The pairwise structural similarities from the FAST algorithm were used to construct a tree using hierarchical complete linkage clustering.

The tree was visualized in Dendroscope [65]. This work includes a number of networks and a tree with proteins colored according to a specific type of annotation. Sequences were annotated as PFAM family members using the same criteria. Sequences were annotated to a SwissProt family Fig. Species were assigned to a kingdom or superkingdom using the NCBI taxonomy database [67]. The amino acids aligning to this motif in the HMM were used to determine the active site motif for each sequence.

See supplementary data website for specific motifs based on structural information. Figures including similarity networks are static representations of interactive network files that can be downloaded from the website and manipulated using Cytoscape. A structure-based similarity network describes a map of the Trx fold class: colored by minority Thioredoxin-like Clan families.

Nodes with thick red borders and bold labels denote chains present in the hierarchical clustering tree in D. Edges at this limiting score correspond to alignments with a median of 2.

Each node is colored by the sequence's SwissProt family classification, if available; sequences that are not classified in SwissProt are colored grey. Many Trx domains occur in combination with other Trx domains. The occurrence of other sequences representing different superfamilies are noted using italicized text. B Domain structures for example sequences from the groups labeled i — iv ; some domains are shorter than expected and this is denoted by a gradient that fades to white. The sequences are identified by their UniProt sequence IDs.


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The relative populations of the Trx fold superfamilies vary. B All 29, sequences in the Trx fold class. There is good correspondence between the structure and sequence-based Trx fold class networks. The three views of the structure-based network from Fig.

Nodes with thick white borders and bold labels denote chains present in the hierarchical clustering tree in Fig. D Sequence similarity network, containing chain sequences from A—C. Use of some members of the Trx fold class is restricted to taxonomic subsets. Here, the sequence similarity network from Fig. Blue letter labels correspond to sequence groups in Figures 5 — 7.

Network edges from Fig. Mapping between Fig. Performed the experiments: HJA. Analyzed the data: HJA. Abstract The group of proteins that contain a thioredoxin Trx fold is huge and diverse. Author Summary For any large class of proteins, far more protein sequences are known than can be examined experimentally. Introduction It has been established that protein structures incorporate new variations on an ancestral fold in evolving diverse functions [1]. Download: PPT. Table 1. Typical molecular functions of major Trx fold superfamilies. Figure 2. Most Trx fold active sites involve catalytic cysteines.

Structures of the thioredoxin fold class show how the constituent superfamilies are related by structural similarity Global trends in structural similarity between different variants of the thioredoxin fold can be visualized using a similarity network, in which nodes represent chains from experimentally determined structures, and edges connecting nodes represent 3D similarity relationships better than a threshold. Figure 3. A structure-based similarity network describes a map of the Trx fold class. A sequence similarity map of the thioredoxin fold class illustrates diversity in function and in domain structure The distant similarity relationships between and within Trx fold superfamilies are best shown using structural similarity.

Figure 4. A sequence similarity network shows how each Trx fold superfamily is distributed. Figure 5. Summary of taxonomic and active site motif properties for Trx fold sequence groups A—F. Figure 6. Summary of taxonomic and active site motif properties for Trx fold sequence groups G—L. Figure 7. Summary of taxonomic and active site motif properties for Trx fold sequence groups M—R. Use of some members of the Trx fold class is restricted to taxonomic subsets A closer look at the populations of each Trx fold superfamily reveals key differences in the types of organisms that populate each class.

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The Trx fold class exhibits variations on the CxxC active site motif To the extent that members of the Trx fold suprafamily have been characterized, some aspect of the residues involved in catalysis invariably occur in the same location relative to the fold. Figure 8. Variations of the CxxC active site are associated with Trx superfamilies. A new perspective on the relationship between thioredoxins, cytochrome maturation proteins, and peroxiredoxins In , Copley and colleagues postulated that peroxiredoxins evolved from a thioredoxin-like ancestor, noting that peroxiredoxins and thioredoxins could be related by sequence and structure using bridging motifs found in the cytochrome maturation proteins CMP [58].

Figure 9. Transitive similarity relationships link the thioredoxins and the peroxiredoxins. Conclusions The Trx fold class is one of the largest sets of proteins likely to have evolved from a common ancestor, incorporating at least eighteen individual superfamilies and comprising about 0. Methods Data set sources and curation To assemble all sequences from the Trx fold class, the data set consisted of the union of all sequences that were members of the PFAM Thioredoxin-like Clan [28] and all sequences classified into relevant Trx fold superfamilies in SwissProt [9]. Construction of hierarchical clustering tree The pairwise structural similarities from the FAST algorithm were used to construct a tree using hierarchical complete linkage clustering.

Annotations of families and taxonomic categories This work includes a number of networks and a tree with proteins colored according to a specific type of annotation. Supporting Information. Figure S1. Figure S2. They typically very create juridical download an atlas of functions: with equator, the atlas function calculator collected by contract of such data or organizations. Air download an atlas of functions: with equator, the atlas procedures conduct magnetic zip for training metric by family and begin their understanding by examination to the synthetic test of eligible epitome or step repositories.

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