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Characteristics of EFR and functional residues.
No full textEFR (dark blue) and LFR (light blue) are compared to functional (dark orange) and non-functional (light orange) residues. The notch of a box corresponds to the confidence interval around its median: two notches which do not overlap indicate a difference of medians. (A) EFR show lower computed energies than they are in contact with many residues and tend to be embedded in the hydrophobic core. In contrast, functional residues are exposed to the solvent in order to constitute e.g. binding sites. (B) Hydrophobic interactions occur especially in the core of a protein, thus, most residues do not form any. However, EFR show a significant increase compared to LFR. (C) The clustering coefficient of a node describes how well-connected its adjacent nodes are. EFR connect regions of a protein which are separated at sequence level and, thus, are not well-connected on their own. Functional residues exhibit higher clustering coefficient indicating a more connected set of adjacent nodes.</p
Schematic representation of protozyme regions.
No full textThe two classes of contemporary aaRS enzymes may originate from opposite strands of the same gene. The corresponding peptides (called protozymes) have been shown to be catalytically active [43, 46]. The order of secondary structure elements in both protozymes resembles a mirror image. Using the EFoldMine classifier [9], EFR (i.e. folding initiation sites) were predicted (depicted in blue). EFR are a distinct set of residues with respect to ATP binding sites (orange) identified in a previous study [48]. Backbone Brackets and Arginine Tweezers are class-specific ATP binding motifs identified in the same study. Regardless of aaRS class, EFR occur in the center of secondary structure elements. Their position is preserved within aaRS classes despite sequence conservation being relatively small. The relative arrangement of EFR in class I resembles a prominent structural packing motif [50]. The more general Start2Fold dataset [41] is used to assess whether the separation of EFR and functional residues is a common theme in protein structures. The ATP binding region contains four binding residues each and was simplified to a continuous region for visual simplicity. Figure adapted from [46, 48].</p
Characterizing the relation of functional and Early Folding Residues in protein structures using the example of aminoacyl-tRNA synthetases
No full textProteins are chains of amino acids which adopt a three-dimensional structure and are then able to catalyze chemical reactions or propagate signals in organisms. Without external influence, many proteins fold into their native structure, and a small number of Early Folding Residues (EFR) have previously been shown to initiate the formation of secondary structure elements and guide their respective assembly. Using the two diverse superfamilies of aminoacyl-tRNA synthetases (aaRS), it is shown that the position of EFR is preserved over the course of evolution even when the corresponding sequence conservation is small. Folding initiation sites are positioned in the center of secondary structure elements, independent of aaRS class. In class I, the predicted position of EFR resembles an ancient structural packing motif present in many seemingly unrelated proteins. Furthermore, it is shown that EFR and functionally relevant residues in aaRS are almost entirely disjoint sets of residues. The Start2Fold database is used to investigate whether this separation of EFR and functional residues can be observed for other proteins. EFR are found to constitute crucial connectors of protein regions which are distant at sequence level. Especially, these residues exhibit a high number of non-covalent residue-residue contacts such as hydrogen bonds and hydrophobic interactions. This tendency also manifests as energetically stable local regions, as substantiated by a knowledge-based potential. Despite profound differences regarding how EFR and functional residues are embedded in protein structures, a strict separation of structurally and functionally relevant residues cannot be observed for a more general collection of proteins.</div
Topological properties of EFR and LFR.
No full textProteins were represented as residue graphs and a network analysis was performed. The notch of a box corresponds to the confidence interval around its median: two notches which do not overlap indicate a difference of medians. (A) EFR have higher betweenness values implying that shortest paths in the graph tend to pass through these nodes more often. (B) They also exhibit higher closeness values because their average path length to other nodes is lower on average. (C) The distinct neighborhood count of a residue describes to how many separated regions it is connected. Residues are considered separated when their separation at sequence level is greater than five. EFR connect significantly more distant regions of a protein than LFR.</p
Comparison of folding characteristics and functional relevance for aaRS classes.
No full textComparison of folding characteristics and functional relevance for aaRS classes.</p
Binding site of aaRS enzymes.
No full textFor the annotation of functional residues [48] the ligand binding site of aaRS structures was assessed. ATP binding (dark orange) is uniform within each aaRS class, whereas the amino acid binding (light orange) is specific to particular aaRS types such as AspRS. Figure adapted from [48].</p
Protozyme regions of both aaRS classes.
No full textThe protozyme regions [46–48] (in cartoon style) and the respective aminoacyl-AMP ligand (in sticks style) are depicted. This captures the state after the first reaction, when ATP and amino acid have been covalently bound. The ATP part is oriented to the left, whereas the amino acid is located on the right. Residues predicted to be Early Folding [9] are colored blue, whereas functional residues [48] are rendered in orange. ATP interaction sites are depicted in dark orange, residue positions observed to interact with the amino acid in any aaRS structure are rendered in light orange. In the rare cases that residues are both EFR and functional, they bind the amino acid part of the ligand in two specific aaRS types. (A) The class I protozyme is represented by truncated PDB:1euy_A. The respective EFR are located in the center of the ordered secondary structure elements and resemble a common structural packing motif that has been identified by Cammer & Carter [50]. In contrast, functional ligand binding sites are located in the upper part of each subfigure. They are primarily located in unordered coil regions. (B) The class II protozyme (represented by truncated PDB:1c0a_A) shows similar tendencies.</p
Rendered structures of 2 dataset entries.
No full textEFR are rendered in blue, functional residues are rendered in orange. (A) In the case of trypsin inhibitor (PDB:5pti_A) the intersection of EFR and functional residues is empty. For many proteins in the dataset, there is a clear distinction between both classes and structurally relevant residues have a propensity to be located in the core, while functional residues are exposed on the surface of a protein. (B) Five residues are both EFR and functional in the acyl-coenzyme A binding protein (PDB:2abd_A) which is one of the cases in the dataset where many residues are both EFR as well as functional.</p
Contingency table of folding characteristics and functional relevance.
No full textContingency table of folding characteristics and functional relevance.</p
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