Cradle-loop barrels and the concept of metafolds in protein classification by natural descent Vikram Alva , Kristin K Koretke , Murray Coles and Andrei N Lupas

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/
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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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    • "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.
    PLoS ONE 10/2013; 8(10):e77074. DOI:10.1371/journal.pone.0077074 · 3.23 Impact Factor
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    • "Author's personal copy Table 2 The Drosophila Tight-binding Inhibitors. MEROPS Family Gene name FlyBase identifier AAs Domains Biological function/comment mRNA regulation Reference I1 Kazal CG31704 68 S þ I.C [28] CG14933 77 S CG42486 77 S CG17278 80 S Wnt receptor signalling þ I.C [30,78] Kaz1-B CG1220 97 S Sfp33A3 CG42474 99 S Seminal fluid protein Kaz1-A CG33790 103 S CG7695 145 S E(spl)m1 CG8342 165 S CG7906 354 C (2x) Ecdysone induced [30] CG7924 321 C (2x) Ecdysone Induced CG12716 418 S CG7173 564 C CG31758 605 Cx Cyclic nucleotide magu CG2264 613 Cx Longevity [46] CG13830 629 Cx CG32354 662 C (5x) Oatp58a CG30277 684 Cx Org. anion transport Oatp26F CG11332 692 Cx Org. "
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    ABSTRACT: Proteolytic signalling cascades control a wide range of physiological responses. In order to respond rapidly, protease activity must be maintained at a basal level: the component zymogens must be sequentially activated and actively degraded. At the same time, signalling cascades must respond precisely: high target specificity is required. The insects have a wide range of trapping- and tight-binding protease inhibitors, which can regulate the activity of individual proteases. In addition, the interactions between component proteases of a signalling cascade can be modified by serine protease homologues. The suicide-inhibition mechanism of serpin family inhibitors gives rapid turnover of both protease and inhibitor, but target specificity is inherently broad. Similarly, the TEP/macroglobulins have extremely broad target specificity, which suits them for roles as hormone transport proteins and sensors of pathogenic virulence factors. The tight-binding inhibitors, on the other hand, have a lock-and-key mechanism capable of high target specificity. In addition, proteins containing multiple tight-binding inhibitory domains may act as scaffolds for the assembly of signalling complexes. Proteolytic cascades regulated by combinations of different types of inhibitor could combine the rapidity of suicide-inhibitors with the specificity lock-and-key inhibitors. This would allow precise control of physiological responses and may turn out to be a general rule.
    Biochimie 12/2010; 92(12):1749-59. DOI:10.1016/j.biochi.2010.09.004 · 2.96 Impact Factor
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    • "structures (Alva et al., 2008). A subset of the representative domains from our v2003 CDD was used to conduct benchmark simulations of molecular dynamics (MD) force fields (Rueda et al., 2007). "
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    ABSTRACT: MOTIVATION: The discovery of new protein folds is a relatively rare occurrence even as the rate of protein structure determination increases. This rarity reinforces the concept of folds as reusable units of structure and function shared by diverse proteins. If the folding mechanism of proteins is largely determined by their topology, then the folding pathways of members of existing folds could encompass the full set used by globular protein domains. RESULTS: We have used recent versions of three common protein domain dictionaries (SCOP, CATH and Dali) to generate a consensus domain dictionary (CDD). Surprisingly, 40% of the metafolds in the CDD are not composed of autonomous structural domains, i.e. they are not plausible independent folding units. This finding has serious ramifications for bioinformatics studies mining these domain dictionaries for globular protein properties. However, our main purpose in deriving this CDD was to generate an updated CDD to choose targets for MD simulation as part of our dynameomics effort, which aims to simulate the native and unfolding pathways of representatives of all globular protein consensus folds (metafolds). Consequently, we also compiled a list of representative protein targets of each metafold in the CDD. Availability and implementation: This domain dictionary is available at
    Bioinformatics 11/2010; 27(1):46-54. DOI:10.1093/bioinformatics/btq625 · 4.98 Impact Factor
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