New β-Propellers Are Continuously Amplified From Single Blades in all Major Lineages of the β-Propeller Superfamily.
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ABSTRACT:
SUBMITTER: Pereira J
PROVIDER: S-EPMC9218822 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:?-Propellers arise through the amplification of a supersecondary structure element called a blade. This process produces toroids of between four and twelve repeats, which are almost always arranged sequentially in a single polypeptide chain. We found that new propellers evolve continuously by amplification from single blades. We therefore investigated whether such nascent propellers can fold as homo-oligomers before they have been fully amplified within a single chain. One- to six-bladed building blocks derived from two seven-bladed WD40 propellers yielded stable homo-oligomers with six to nine blades, depending on the size of the building block. High-resolution structures for tetramers of two blades, trimers of three blades, and dimers of four and five blades, respectively, show structurally diverse propellers and include a novel fold, highlighting the inherent flexibility of the WD40 blade. Our data support the hypothesis that subdomain-sized fragments can provide structural versatility in the evolution of new proteins.
| S-EPMC6805158 | biostudies-literature
Project description:Proteins of the ?-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 ?-meanders, the so called blades that are arranged circularly around a central funnel-shaped pore. Despite the large size range of ?-propellers, their blades frequently show sequence similarity indicative of a common ancestry and it has been proposed that the majority of ?-propellers arose divergently by amplification and diversification of an ancestral blade. Given the structural versatility of ?-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 ?-propellers: the luminal domain of inositol-requiring enzyme 1 (IRE1-LD), type II ?-prisms, ?-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 ?-prisms with ?-propellers, and an analogous one for ?-pinwheels and WW domains. Whereas IRE1-LD most likely originated by fold-changing mutations from a fully formed PQQ motif ?-propeller, type II ?-prisms originated by amplification and differentiation of a single blade, possibly also of the PQQ type. We conclude that both ?-propellers and type II ?-prisms arose by independent amplification of a blade-sized fragment, which represents a remnant of an ancient peptide world.
| S-EPMC3797127 | biostudies-literature
Project description:Motivationβ-Propellers are found in great variety across all kingdoms of life. They assume many cellular roles, primarily as scaffolds for macromolecular interactions and catalysis. Despite their diversity, most β-propeller families clearly originated by amplification from the same ancient peptide-the "blade". In cluster analyses, β-propellers of the WD40 superfamily always formed the largest group, to which some important families, such as the α-integrin, Asp-box, and glycoside hydrolase β-propellers connected weakly. Motivated by the dramatic growth of sequence databases we revisited these connections, with a special focus on VCBS-like β-propellers, which have not been analysed for their evolutionary relationships so far.ResultsWe found that VCBS-like form a supercluster with integrin-like β-propellers and tachylectins, clearly delimited from the superclusters formed by WD40 and Asp-Box β-propellers. Connections between the three superclusters are made mainly through PQQ-like β-propeller. Our results present a new, greatly expanded view of the β-propeller classification landscape.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC8023676 | biostudies-literature
Project description:The lipoprotein receptor (LR) family constitutes a large group of structurally closely related receptors with broad ligand-binding specificity. Traditionally, ligand binding to LRs has been anticipated to involve merely the complement type repeat (CR)-domains omnipresent in the family. Recently, this dogma has transformed with the observation that β-propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the β-propellers as binding targets depends on receptor subgroups. In particular, we highlight the shutter mechanism of β-propellers as a general recognition motif for NxI-containing ligands, and we present indications that the generalized β-propeller-induced ligand release mechanism is not applicable for the larger LRs. For the giant LR members, we present evidence that their β-propellers may also actively engage in ligand binding. We therefore advocate for an increased focus on solving the structure-function relationship of this group of important biological receptors.
| S-EPMC3770089 | biostudies-literature
Project description:BackgroundThe Asp-box is a short sequence and structure motif that folds as a well-defined beta-hairpin. It is present in different folds, but occurs most prominently as repeats in beta-propellers. Asp-box beta-propellers are known to be characteristically irregular and to occur in many medically important proteins, most of which are glycosidase enzymes, but they are otherwise not well characterized and are only rarely treated as a distinct beta-propeller family. We have analyzed the sequence, structure, function and occurrence of the Asp-box and s-Asp-box -a related shorter variant, and provide a comprehensive classification and computational analysis of the Asp-box beta-propeller family.ResultsWe find that all conserved residues of the Asp-box support its structure, whereas the residues in variable positions are generally used for other purposes. The Asp-box clearly has a structural role in beta-propellers and is highly unlikely to be involved in ligand binding. Sequence analysis of the Asp-box beta-propeller family reveals it to be very widespread especially in bacteria and suggests a wide functional range. Disregarding the Asp-boxes, sequence conservation of the propeller blades is very low, but a distinct pattern of residues with specific properties have been identified. Interestingly, Asp-boxes are occasionally found very close to other propeller-associated repeats in extensive mixed-motif stretches, which strongly suggests the existence of a novel class of hybrid beta-propellers. Structural analysis reveals that the top and bottom faces of Asp-box beta-propellers have striking and consistently different loop properties; the bottom is structurally conserved whereas the top shows great structural variation. Interestingly, only the top face is used for functional purposes in known structures. A structural analysis of the 10-bladed beta-propeller fold, which has so far only been observed in the Asp-box family, reveals that the inner strands of the blades are unusually far apart, which explains the surprisingly large diameter of the central tunnel of sortilin.ConclusionWe have provided new insight into the structure and function of the Asp-box motif and of Asp-box beta-propellers, and expect that the classification and analysis presented here will prove helpful in interpreting future data on Asp-box proteins in general and on Asp-box beta-propellers in particular.
| S-EPMC2716378 | biostudies-literature
Project description:The major facilitator superfamily (MFS) is one of the two largest families of membrane transporters found on Earth. It is present ubiquitously in bacteria, archaea, and eukarya and includes members that can function by solute uniport, solute/cation symport, solute/cation antiport and/or solute/solute antiport with inwardly and/or outwardly directed polarity. All homologous MFS protein sequences in the public databases as of January 1997 were identified on the basis of sequence similarity and shown to be homologous. Phylogenetic analyses revealed the occurrence of 17 distinct families within the MFS, each of which generally transports a single class of compounds. Compounds transported by MFS permeases include simple sugars, oligosaccharides, inositols, drugs, amino acids, nucleosides, organophosphate esters, Krebs cycle metabolites, and a large variety of organic and inorganic anions and cations. Protein members of some MFS families are found exclusively in bacteria or in eukaryotes, but others are found in bacteria, archaea, and eukaryotes. All permeases of the MFS possess either 12 or 14 putative or established transmembrane alpha-helical spanners, and evidence is presented substantiating the proposal that an internal tandem gene duplication event gave rise to a primordial MFS protein prior to divergence of the family members. All 17 families are shown to exhibit the common feature of a well-conserved motif present between transmembrane spanners 2 and 3. The analyses reported serve to characterize one of the largest and most diverse families of transport proteins found in living organisms.
| S-EPMC98904 | biostudies-literature
Project description:beta-propeller domains composed of WD repeats are highly ubiquitous and typically used as multi-site docking platforms to coordinate and integrate the activities of groups of proteins. Here, we have used extensive homology modelling of the WD40-repeat family of seven-bladed beta-propellers coupled with subsequent structural classification and clustering of these models to define subfamilies of beta-propellers with common structural, and probable, functional characteristics. We show that it is possible to assign seven-bladed WD beta-propeller proteins into functionally different groups based on the information gained from homology modelling. We examine general structural diversity within the WD40-repeat family of seven-bladed beta-propellers and demonstrate that seven-bladed beta-propellers composed of WD-repeats are structurally distinct from other seven-bladed beta-propellers. We further provide some insights into the multifunctional diversity of the seven-bladed WD beta-propeller surfaces. This report once again reinforces the importance of structural data and the usefulness of homology models in functional classification.
| S-EPMC2614187 | biostudies-literature
Project description:BACKGROUND: Identifying the regions associated with protein function is a singularly important task in the post-genomic era. Biological studies often identify functional enzyme residues by amino acid sequences, particularly when related structural information is unavailable. In some cases of protein superfamilies, functional residues are difficult to detect by current alignment tools or evolutionary strategies when phylogenetic relationships do not parallel their protein functions. The solution proposed in this study is Feature Amplified Voting Algorithm with Three-profile alignment (FAVAT). The core concept of FAVAT is to reveal the desired features of a target enzyme or protein by voting on three different property groups aligned by three-profile alignment method. Functional residues of a target protein can then be retrieved by FAVAT analysis. In this study, the amidohydrolase superfamily was an interesting case for verifying the proposed approach because it contains divergent enzymes and proteins. RESULTS: The FAVAT was used to identify critical residues of mammalian imidase, a member of the amidohydrolase superfamily. Members of this superfamily were first classified by their functional properties and sources of original organisms. After FAVAT analysis, candidate residues were identified and compared to a bacterial hydantoinase in which the crystal structure (1GKQ) has been fully elucidated. One modified lysine, three histidines and one aspartate were found to participate in the coordination of metal ions in the active site. The FAVAT analysis also redressed the misrecognition of metal coordinator Asp57 by the multiple sequence alignment (MSA) method. Several other amino acid residues known to be related to the function or structure of mammalian imidase were also identified. CONCLUSIONS: The FAVAT is shown to predict functionally important amino acids in amidohydrolase superfamily. This strategy effectively identifies functionally important residues by analyzing the discrepancy between the sequence and functional properties of related proteins in a superfamily, and it should be applicable to other protein families.
| S-EPMC2999344 | biostudies-literature
Project description:β-Propeller proteins form one of the largest families of protein structures, with a pseudo-symmetrical fold made up of subdomains called blades. They are not only abundant but are also involved in a wide variety of cellular processes, often by acting as a platform for the assembly of protein complexes. WD40 proteins are a subfamily of propeller proteins with no intrinsic enzymatic activity, but their stable, modular architecture and versatile surface have allowed evolution to adapt them to many vital roles. By computationally reverse-engineering the duplication, fusion and diversification events in the evolutionary history of a WD40 protein, a perfectly symmetrical homologue called Tako8 was made. If two or four blades of Tako8 are expressed as single polypeptides, they do not self-assemble to complete the eight-bladed architecture, which may be owing to the closely spaced negative charges inside the ring. A different computational approach was employed to redesign Tako8 to create Ika8, a fourfold-symmetrical protein in which neighbouring blades carry compensating charges. Ika2 and Ika4, carrying two or four blades per subunit, respectively, were found to assemble spontaneously into a complete eight-bladed ring in solution. These artificial eight-bladed rings may find applications in bionanotechnology and as models to study the folding and evolution of WD40 proteins.
| S-EPMC6327176 | biostudies-literature
Project description:BackgroundBeta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes.MethodsA total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2.ResultsOverall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests.ConclusionOur data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.
| S-EPMC9613602 | biostudies-literature