Dataset Information

New β-Propellers Are Continuously Amplified From Single Blades in all Major Lineages of the β-Propeller Superfamily.

ABSTRACT: β-Propellers are toroidal folds, in which consecutive supersecondary structure units of four anti-parallel β-strands-called blades-are arranged radially around a central axis. Uniquely among toroidal folds, blades span the full range of sequence symmetry, from near identity to complete divergence, indicating an ongoing process of amplification and differentiation. We have proposed that the major lineages of β-propellers arose through this mechanism and that therefore their last common ancestor was a single blade, not a fully formed β-propeller. Here we show that this process of amplification and differentiation is also widespread within individual lineages, yielding β-propellers with blades of more than 60% pairwise sequence identity in most major β-propeller families. In some cases, the blades are nearly identical, indicating a very recent amplification event, but even in cases where such recently amplified β-propellers have more than 80% overall sequence identity to each other, comparison of their DNA sequence shows that the amplification occurred independently.

SUBMITTER: Pereira J

PROVIDER: S-EPMC9218822 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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New β-Propellers Are Continuously Amplified From Single Blades in all Major Lineages of the β-Propeller Superfamily.

Pereira Joana J Lupas Andrei N AN

Frontiers in molecular biosciences 20220609

β-Propellers are toroidal folds, in which consecutive supersecondary structure units of four anti-parallel β-strands-called blades-are arranged radially around a central axis. Uniquely among toroidal folds, blades span the full range of sequence symmetry, from near identity to complete divergence, indicating an ongoing process of amplification and differentiation. We have proposed that the major lineages of β-propellers arose through this mechanism and that therefore their last common ancestor w ...[more]

PMID: 35755816

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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.

Project description:BackgroundIdentifying 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.ResultsThe 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.ConclusionsThe 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.

Dataset Information

New β-Propellers Are Continuously Amplified From Single Blades in all Major Lineages of the β-Propeller Superfamily.

Publications

New β-Propellers Are Continuously Amplified From Single Blades in all Major Lineages of the β-Propeller Superfamily.

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