Evolutionary motif and its biological and structural significance

The accuracy of multiple sequence alignment program MAFFT has been improved. The new version (5.3) of MAFFT offers new iterative refinement options, H-INS-i, F-INS-i and G-INS-i, in which pairwise alignment information are incorporated into objective function. These new options of MAFFT showed higher accuracy than currently available methods including TCoffee version 2 and CLUSTAL W in benchmark tests consisting of alignments of >50 sequences. Like the previously available options, the new options of MAFFT can handle hundreds of sequences on a standard desktop computer. We also examined the effect of the number of homologues included in an alignment. For a multiple alignment consisting of ∼8 sequences with low similarity, the accuracy was improved (2–10 percentage points) when the sequences were aligned together with dozens of their close homologues (E-value < 10−5–10−20) collected from a database. Such improvement was generally observed for most methods, but remarkably large for the new options of MAFFT proposed here. Thus, we made a Ruby script, mafftE.rb, which aligns the input sequences together with their close homologues collected from SwissProt using NCBI-BLAST.

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“… f Guide tree is recalculated based on the first alignment and progressive alignment is re-performed (1,13). …”

Section: Figures and Tablesmentioning

confidence: 99%

“…The initial distance matrix is less reliable than that based on all pairwise alignments. We can obtain more reliable distance matrix by using the FFT-NS-1 alignment (1,11,13). Progressive alignment is re-performed based on the new tree calculated from the new distance matrix.…”

Section: Introductionmentioning

confidence: 99%

MAFFT version 5: improvement in accuracy of multiple sequence alignment

Katoh

Kuma²,

Toh³

et al. 2005

Nucleic Acids Research

4,393

3,453

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“…Structural symmetry is observed in many different protein architectures, and gene duplication and fusion is the generally hypothesized mechanism for the emergence of symmetric architecture from simpler (i.e., archaic) peptide motifs (1)(2)(3)(4). Such motifs, believed to represent the translational product of "genes of primordial life" (5), typically code for polypeptides of ∼40-60 residues in length (5,6) and may define elemental folding units (i.e., "foldons") (7). Two distinctly different evolutionary models for the emergence of symmetric protein architecture from a primordial peptide motif have been proposed (8)(9)(10)(11)(12)(13).…”

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confidence: 99%

Experimental support for the evolution of symmetric protein architecture from a simple peptide motif

Lee

Blaber²

2010

Proc. Natl. Acad. Sci. U.S.A.

102

140

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The majority of protein architectures exhibit elements of structural symmetry, and "gene duplication and fusion" is the evolutionary mechanism generally hypothesized to be responsible for their emergence from simple peptide motifs. Despite the central importance of the gene duplication and fusion hypothesis, experimental support for a plausible evolutionary pathway for a specific protein architecture has yet to be effectively demonstrated. To address this question, a unique "top-down symmetric deconstruction" strategy was utilized to successfully identify a simple peptide motif capable of recapitulating, via gene duplication and fusion processes, a symmetric protein architecture (the threefold symmetric β-trefoil fold). The folding properties of intermediary forms in this deconstruction agree precisely with a previously proposed "conserved architecture" model for symmetric protein evolution. Furthermore, a route through foldable sequence-space between the simple peptide motif and extant protein fold is demonstrated. These results provide compelling experimental support for a plausible evolutionary pathway of symmetric protein architecture via gene duplication and fusion processes.protein design | protein folding | protein symmetry

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“…Yeast surface display (YSD) or phage display combined with high-throughput sequencing is one of the most successful approaches for protein-ligand discovery, mutational scanning, or protein engineering. Examples of their applications include the identification of glucocorticoid receptors 5 , phage receptors 6 , targets of drugs or inhibitors 7 , vaccine targets 8 , T-cell receptors 9 , and antibody targets 10 . YSD entails the expression of exogenous proteins encoded by DNA libraries on the surface of yeast cells.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide libraries for protozoan pathogens drug target screening using yeast surface display

Heslop

Gao

Lira

et al. 2022

Preprint

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The lack of genetic tools to manipulate protozoan pathogens has limited the use of genome-wide approaches to identify drug or vaccine targets and understand these organisms' biology. We have developed an efficient method to construct genome-wide libraries for yeast surface display (YSD) and developed a YSD fitness screen (YSD-FS) to identify drug targets. We show the robustness of our method by generating genome-wide libraries forTrypanosoma brucei,Trypanosoma cruzi, andGiardia lambliaparasites. Each library has a diversity of ~105to 106clones, representing ~6 to 30-fold of the parasite's genome. Nanopore sequencing confirmed the libraries' genome coverage with multiple clones for each parasite gene. Western blot and imaging analysis confirmed surface expression of theG. lamblialibrary proteins in yeast. Using the YSD-FS assay, we identified bonafide interactors of metronidazole, a drug used to treat protozoan and bacterial infections. We also found enrichment in nucleotide-binding domain sequences associated with yeast increased fitness to metronidazole, indicating that this drug might target multiple enzymes containing nucleotide-binding domains. The libraries are valuable biological resources for discovering drug or vaccine targets, ligand receptors, protein-protein interactions, and pathogen-host interactions. The library assembly approach can be applied to other organisms or expression systems, and the YSD-FS assay might help identify new drug targets in protozoan pathogens.

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Evolutionary motif and its biological and structural significance

Cited by 13 publications

References 24 publications

MAFFT version 5: improvement in accuracy of multiple sequence alignment

MAFFT version 5: improvement in accuracy of multiple sequence alignment

Experimental support for the evolution of symmetric protein architecture from a simple peptide motif

Genome-wide libraries for protozoan pathogens drug target screening using yeast surface display

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