Cradle-loop barrels and the concept of metafolds in protein classification by natural descent

Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Spemannstr. 35, D-72076 Tübingen, Germany.
Current Opinion in Structural Biology (Impact Factor: 7.2). 07/2008; 18(3):358-65. DOI: 10.1016/
Source: PubMed


Current classification systems for protein structure show many inconsistencies both within and between systems. The metafold concept was introduced to identify fold similarities by consensus and thus provide a more unified view of fold space. Using cradle-loop barrels as an example, we propose to use the metafold as the next hierarchical level above the fold, encompassing a group of topologically related folds for which a homologous relationship has been substantiated. We see this as an important step on the way to a classification of proteins by natural descent.

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Available from: Andrei Lupas, Aug 30, 2014
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    • "A fragment was deemed to interact with these molecules if it made at least three inter-atomic contacts to them within a distance cut-off of 3Å . In addition, we included one of our fragments, the b-a-b motif seen in cradle-loop barrels (Alva et al., 2008) (Fig- ure 3: 7) into the nucleic acid binding set, even though only a high-resolution model of its interaction with DNA is currently available, based on NMR data (Zorzini et al., 2015). Even discounting this addition, the 12 other nucleic acid-binding fragments of our set substantially exceed the two nucleic acid binders found in the Smotifs set, even though these cover about three times as many superfamilies and folds. "
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    ABSTRACT: The seemingly limitless diversity of proteins in nature arose from only a few thousand domain prototypes, but the origin of these themselves has remained unclear. We are pursuing the hypothesis that they arose by fusion and accretion from an ancestral set of peptides active as co-factors in RNA-dependent replication and catalysis. Should this be true, contemporary domains may still contain vestiges of such peptides, which could be reconstructed by a comparative approach in the same way in which ancient vocabularies have been reconstructed by the comparative study of modern languages. To test this, we compared domains representative of known folds and identified 40 fragments whose similarity is indicative of common descent, yet which occur in domains currently not thought to be homologous. These fragments are widespread in the most ancient folds and enriched for iron-sulfur- and nucleic acid-binding. We propose that they represent the observable remnants of a primordial RNA-peptide world.
    Full-text · Article · Dec 2015 · eLife Sciences
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    • "Even remote homologs often still adopt the same fold, however in some instances homology could be established for proteins of different folds. These homologies were either established by the detection of homologous fold change [1]–[4] or by evidence for shared conserved supersecondary structures [4]–[8]. The latter are assumed to be remnants of an ancient peptide-RNA world [9]–[13]. "
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    ABSTRACT: Proteins of the β-propeller fold are ubiquitous in nature and widely used as structural scaffolds for ligand binding and enzymatic activity. This fold comprises between four and twelve four-stranded β-meanders, the so called blades that are arranged circularly around a central funnel-shaped pore. Despite the large size range of β-propellers, their blades frequently show sequence similarity indicative of a common ancestry and it has been proposed that the majority of β-propellers arose divergently by amplification and diversification of an ancestral blade. Given the structural versatility of β-propellers and the hypothesis that the first folded proteins evolved from a simpler set of peptides, we investigated whether this blade may have given rise to other folds as well. Using sequence comparisons, we identified proteins of four other folds as potential homologs of β-propellers: the luminal domain of inositol-requiring enzyme 1 (IRE1-LD), type II β-prisms, β-pinwheels, and WW domains. Because, with increasing evolutionary distance and decreasing sequence length, the statistical significance of sequence comparisons becomes progressively harder to distinguish from the background of convergent similarities, we complemented our analyses with a new method that evaluates possible homology based on the correlation between sequence and structure similarity. Our results indicate a homologous relationship of IRE1-LD and type II β-prisms with β-propellers, and an analogous one for β-pinwheels and WW domains. Whereas IRE1-LD most likely originated by fold-changing mutations from a fully formed PQQ motif β-propeller, type II β-prisms originated by amplification and differentiation of a single blade, possibly also of the PQQ type. We conclude that both β-propellers and type II β-prisms arose by independent amplification of a blade-sized fragment, which represents a remnant of an ancient peptide world.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Consider the example of the GD box (Alva et al., 2009). The GD box links remotely homologous members of the cradle-loop barrel metafold (Alva et al., 2008) but also otherwise unrelated folds sharing an analogous motif. HHfrag detects GD boxes with very high coverage and precision. "
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    ABSTRACT: MOTIVATION: Over the last decade, both static and dynamic fragment libraries for protein structure prediction have been introduced. The former are built from clusters in either sequence or structure space and aim to extract a universal structural alphabet. The latter are tailored for a particular query protein sequence and aim to provide local structural templates that need to be assembled in order to build the full-length structure. RESULTS: Here, we introduce HHfrag, a dynamic HMM-based fragment search method built on the profile-profile comparison tool HHpred. We show that HHfrag provides advantages over existing fragment assignment methods in that it: (i) improves the precision of the fragments at the expense of a minor loss in sequence coverage; (ii) detects fragments of variable length (6-21 amino acid residues); (iii) allows for gapped fragments and (iv) does not assign fragments to regions where there is no clear sequence conservation. We illustrate the usefulness of fragments detected by HHfrag on targets from most recent CASP.
    Full-text · Article · Sep 2011 · Bioinformatics
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