Impact of substituent effects on the design of β-sheet mimetics and β-double helices from (E)-vinylogous γ-amino acid oligomers

The unique structures formed by β-amino acid oligomers, or β-peptide foldamers, have been studied for almost two decades, which has led to the discovery of several distinctive structures and bioactive molecules. Recently, this area of research has expanded from conventional peptide drug design to the formation of assemblies and nanomaterials by peptide self-assembly. The unique structures formed by β-peptides give rise to a set of new materials with altered properties that differ from conventional peptide-based materials; such new materials may be useful in several bio- and nanomaterial applications.

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HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires

Vaccines ◽

10.3390/vaccines9030270 ◽

2021 ◽

Vol 9 (3) ◽

pp. 270

Author(s):

Nicky de Vrij ◽

Pieter Meysman ◽

Sofie Gielis ◽

Wim Adriaensen ◽

Kris Laukens ◽

...

Keyword(s):

Amino Acid ◽

Cell Epitope ◽

Human Leukocyte ◽

Leishmania Species ◽

Hla Polymorphism ◽

Common Amino Acid ◽

Binding Core ◽

Epitope Discovery ◽

Epitope Binding ◽

The Impact

Susceptibility for leishmaniasis is largely dependent on host genetic and immune factors. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors for leishmaniasis, little is known regarding the mechanisms that underpin these associations. To better understand this underlying functionality, we first collected all known leishmaniasis-associated HLA variants in a thorough literature review. Next, we aligned and compared the protection- and risk-associated HLA-DRB1 allele sequences. This identified several amino acid polymorphisms that distinguish protection- from risk-associated HLA-DRB1 alleles. Subsequently, T cell epitope binding predictions were carried out across these alleles to map the impact of these polymorphisms on the epitope binding repertoires. For these predictions, we used epitopes derived from entire proteomes of multiple Leishmania species. Epitopes binding to protection-associated HLA-DRB1 alleles shared common binding core motifs, mapping to the identified HLA-DRB1 amino acid polymorphisms. These results strongly suggest that HLA polymorphism, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes. A set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, was prioritized for further epitope discovery in the search for novel subunit-based vaccines.

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Assessing the Impact of Secondary Structure and Solvent Accessibility on Protein Evolution

Genetics ◽

10.1093/genetics/149.1.445 ◽

1998 ◽

Vol 149 (1) ◽

pp. 445-458 ◽

Cited By ~ 21

Author(s):

Nick Goldman ◽

Jeffrey L Thorne ◽

David T Jones

Keyword(s):

Amino Acid ◽

Secondary Structure ◽

Protein Evolution ◽

Solvent Accessibility ◽

Strong Association ◽

Length Distribution ◽

Parametric Bootstrap ◽

Amino Acid Replacement ◽

Physical Constraints ◽

The Impact

Abstract Empirically derived models of amino acid replacement are employed to study the association between various physical features of proteins and evolution. The strengths of these associations are statistically evaluated by applying the models of protein evolution to 11 diverse sets of protein sequences. Parametric bootstrap tests indicate that the solvent accessibility status of a site has a particularly strong association with the process of amino acid replacement that it experiences. Significant association between secondary structure environment and the amino acid replacement process is also observed. Careful description of the length distribution of secondary structure elements and of the organization of secondary structure and solvent accessibility along a protein did not always significantly improve the fit of the evolutionary models to the data sets that were analyzed. As indicated by the strength of the association of both solvent accessibility and secondary structure with amino acid replacement, the process of protein evolution—both above and below the species level—will not be well understood until the physical constraints that affect protein evolution are identified and characterized.

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Codon harmonization reduces amino acid misincorporation in bacterially expressed P. falciparum proteins and improves their immunogenicity

AMB Express ◽

10.1186/s13568-019-0890-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Neeraja Punde ◽

Jennifer Kooken ◽

Dagmar Leary ◽

Patricia M. Legler ◽

Evelina Angov

Keyword(s):

Protein Structure ◽

Amino Acid ◽

Codon Usage ◽

Dna Sequences ◽

Structural Integrity ◽

Host Cells ◽

Loss Of Function ◽

Species Specific ◽

And Function ◽

The Impact

Abstract Codon usage frequency influences protein structure and function. The frequency with which codons are used potentially impacts primary, secondary and tertiary protein structure. Poor expression, loss of function, insolubility, or truncation can result from species-specific differences in codon usage. “Codon harmonization” more closely aligns native codon usage frequencies with those of the expression host particularly within putative inter-domain segments where slower rates of translation may play a role in protein folding. Heterologous expression of Plasmodium falciparum genes in Escherichia coli has been a challenge due to their AT-rich codon bias and the highly repetitive DNA sequences. Here, codon harmonization was applied to the malarial antigen, CelTOS (Cell-traversal protein for ookinetes and sporozoites). CelTOS is a highly conserved P. falciparum protein involved in cellular traversal through mosquito and vertebrate host cells. It reversibly refolds after thermal denaturation making it a desirable malarial vaccine candidate. Protein expressed in E. coli from a codon harmonized sequence of P. falciparum CelTOS (CH-PfCelTOS) was compared with protein expressed from the native codon sequence (N-PfCelTOS) to assess the impact of codon usage on protein expression levels, solubility, yield, stability, structural integrity, recognition with CelTOS-specific mAbs and immunogenicity in mice. While the translated proteins were expected to be identical, the translated products produced from the codon-harmonized sequence differed in helical content and showed a smaller distribution of polypeptides in mass spectra indicating lower heterogeneity of the codon harmonized version and fewer amino acid misincorporations. Substitutions of hydrophobic-to-hydrophobic amino acid were observed more commonly than any other. CH-PfCelTOS induced significantly higher antibody levels compared with N-PfCelTOS; however, no significant differences in either IFN-γ or IL-4 cellular responses were detected between the two antigens.

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Searching for signatures of positive selection in cytochrome b gene associated with subterranean lifestyle in fast-evolving arvicolines (Arvicolinae, Cricetidae, Rodentia)

BMC Ecology and Evolution ◽

10.1186/s12862-021-01819-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Olga V. Bondareva ◽

Nadezhda A. Potapova ◽

Kirill A. Konovalov ◽

Tatyana V. Petrova ◽

Natalia I. Abramson

Keyword(s):

Amino Acid ◽

Oxidative Phosphorylation ◽

Adaptive Evolution ◽

Complex Structure ◽

Subterranean Rodents ◽

Amino Acid Sequence Variation ◽

Tertiary Protein Structure ◽

Metabolic Performance ◽

The Impact ◽

Subterranean Species

Abstract Background Mitochondrial genes encode proteins involved in oxidative phosphorylation. Variations in lifestyle and ecological niche can be directly reflected in metabolic performance. Subterranean rodents represent a good model for testing hypotheses on adaptive evolution driven by important ecological shifts. Voles and lemmings of the subfamily Arvicolinae (Rodentia: Cricetidae) provide a good example for studies of adaptive radiation. This is the youngest group within the order Rodentia showing the fastest rates of diversification, including the transition to the subterranean lifestyle in several phylogenetically independent lineages. Results We evaluated the signatures of selection in the mitochondrial cytochrome b (cytB) gene in 62 Arvicolinae species characterized by either subterranean or surface-dwelling lifestyle by assessing amino acid sequence variation, exploring the functional consequences of the observed variation in the tertiary protein structure, and estimating selection pressure. Our analysis revealed that: (1) three of the convergent amino acid substitutions were found among phylogenetically distant subterranean species and (2) these substitutions may have an influence on the protein complex structure, (3) cytB showed an increased ω and evidence of relaxed selection in subterranean lineages, relative to non-subterranean, and (4) eight protein domains possess increased nonsynonymous substitutions ratio in subterranean species. Conclusions Our study provides insights into the adaptive evolution of the cytochrome b gene in the Arvicolinae subfamily and its potential implications in the molecular mechanism of adaptation. We present a framework for future characterizations of the impact of specific mutations on the function, physiology, and interactions of the mtDNA-encoded proteins involved in oxidative phosphorylation.

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Tools for the Recognition of Sorting Signals and the Prediction of Subcellular Localization of Proteins From Their Amino Acid Sequences

Frontiers in Genetics ◽

10.3389/fgene.2020.607812 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kenichiro Imai ◽

Kenta Nakai

Keyword(s):

Amino Acid ◽

Subcellular Localization ◽

Amino Acid Sequences ◽

Additional Information ◽

Sorting Signals ◽

Specific Alternative ◽

Cell Type Specific ◽

Future Direction ◽

The Impact ◽

New Algorithms

At the time of translation, nascent proteins are thought to be sorted into their final subcellular localization sites, based on the part of their amino acid sequences (i.e., sorting or targeting signals). Thus, it is interesting to computationally recognize these signals from the amino acid sequences of any given proteins and to predict their final subcellular localization with such information, supplemented with additional information (e.g., k-mer frequency). This field has a long history and many prediction tools have been released. Even in this era of proteomic atlas at the single-cell level, researchers continue to develop new algorithms, aiming at accessing the impact of disease-causing mutations/cell type-specific alternative splicing, for example. In this article, we overview the entire field and discuss its future direction.

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Compositional Determinants of Prion Formation in Yeast

Molecular and Cellular Biology ◽

10.1128/mcb.01140-09 ◽

2009 ◽

Vol 30 (1) ◽

pp. 319-332 ◽

Cited By ~ 113

Author(s):

James A. Toombs ◽

Blake R. McCarty ◽

Eric D. Ross

Keyword(s):

Amino Acid ◽

Amino Acid Composition ◽

Amyloid Formation ◽

Yeast Prion ◽

Hydrophobic Residues ◽

Predictive Methods ◽

Infectious Proteins ◽

Β Sheet ◽

Eukaryotic Genomes

ABSTRACT Numerous prions (infectious proteins) have been identified in yeast that result from the conversion of soluble proteins into β-sheet-rich amyloid-like protein aggregates. Yeast prion formation is driven primarily by amino acid composition. However, yeast prion domains are generally lacking in the bulky hydrophobic residues most strongly associated with amyloid formation and are instead enriched in glutamines and asparagines. Glutamine/asparagine-rich domains are thought to be involved in both disease-related and beneficial amyloid formation. These domains are overrepresented in eukaryotic genomes, but predictive methods have not yet been developed to efficiently distinguish between prion and nonprion glutamine/asparagine-rich domains. We have developed a novel in vivo assay to quantitatively assess how composition affects prion formation. Using our results, we have defined the compositional features that promote prion formation, allowing us to accurately distinguish between glutamine/asparagine-rich domains that can form prion-like aggregates and those that cannot. Additionally, our results explain why traditional amyloid prediction algorithms fail to accurately predict amyloid formation by the glutamine/asparagine-rich yeast prion domains.

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Substituent effects on long-range interactions in the β-sheet structure of oligopeptides

Journal of Molecular Structure THEOCHEM ◽

10.1016/j.theochem.2005.08.031 ◽

2005 ◽

Vol 755 (1-3) ◽

pp. 247-251 ◽

Cited By ~ 12

Author(s):

Viktória Horváth ◽

Zoltán Varga ◽

Attila Kovács

Keyword(s):

Long Range ◽

Substituent Effects ◽

Long Range Interactions ◽

Sheet Structure ◽

Β Sheet

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Nuclear Import of Adenovirus DNA Involves Direct Interaction of Hexon with an N-Terminal Domain of the Nucleoporin Nup214

Journal of Virology ◽

10.1128/jvi.02639-14 ◽

2014 ◽

Vol 89 (3) ◽

pp. 1719-1730 ◽

Cited By ~ 37

Author(s):

Aurélia Cassany ◽

Jessica Ragues ◽

Tinglu Guan ◽

Dominique Bégu ◽

Harald Wodrich ◽

...

Keyword(s):

Amino Acid ◽

Binding Site ◽

Nuclear Import ◽

Viral Genome ◽

Molecular Basis ◽

Nuclear Pore ◽

Viral Dna ◽

Terminal Domain ◽

Cytoplasmic Face ◽

The Impact

ABSTRACTIn this study, we characterized the molecular basis for binding of adenovirus (AdV) to the cytoplasmic face of the nuclear pore complex (NPC), a key step during delivery of the viral genome into the nucleus. We used RNA interference (RNAi) to deplete cells of either Nup214 or Nup358, the two major Phe-Gly (FG) repeat nucleoporins localized on the cytoplasmic side of the NPC, and evaluated the impact on hexon binding and AdV infection. The accumulation of purified hexon trimers or partially disassembled AdV at the nuclear envelope (NE) was observed in digitonin-permeabilized cells in the absence of cytosolic factors. Bothin vitrohexon binding andin vivonuclear import of the AdV genome were strongly reduced in Nup214-depleted cells but still occurred in Nup358-depleted cells, suggesting that Nup214 is a major binding site of AdV during infection. The expression of an NPC-targeted N-terminal domain of Nup214 in Nup214-depleted cells restored the binding of hexon at the NE and the nuclear import of protein VII (pVII), indicating that this region is sufficient to allow AdV binding. We further narrowed the binding site to a 137-amino-acid segment in the N-terminal domain of Nup214. Together, our results have identified a specific region within the N terminus of Nup214 that acts as a direct NPC binding site for AdV.IMPORTANCEAdVs, which have the largest genome of nonenveloped DNA viruses, are being extensively explored for use in gene therapy, especially in alternative treatments for cancers that are refractory to traditional therapies. In this study, we characterized the molecular basis for binding of AdV to the cytoplasmic face of the NPC, a key step for delivery of the viral genome into the nucleus. Our data indicate that a 137-amino-acid region of the nucleoporin Nup214 is a binding site for the major AdV capsid protein, hexon, and that this interaction is required for viral DNA import. These findings provide additional insight on how AdV exploits the nuclear transport machinery for infection. The results could promote the development of new strategies for gene transfer and enhance understanding of the nuclear import of other viral DNA genomes, such as those of papillomavirus or hepatitis B virus that induce specific cancers.

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