LIVIVO - Search results -

Search results

Result 1 - 10 of total 44

Search options

Article ; Online: Fitness Effects of Phenotypic Mutations at Proteome-Scale Reveal Optimality of Translation Machinery.

Landerer, Cedric / Poehls, Jonas / Toth-Petroczy, Agnes

2024 Volume 41, Issue 3

Abstract: Errors in protein translation can lead to non-genetic, phenotypic mutations, including amino acid misincorporations. While phenotypic mutations can increase protein diversity, the systematic characterization of their proteome-wide frequencies and their ... ...

Abstract	Errors in protein translation can lead to non-genetic, phenotypic mutations, including amino acid misincorporations. While phenotypic mutations can increase protein diversity, the systematic characterization of their proteome-wide frequencies and their evolutionary impact has been lacking. Here, we developed a mechanistic model of translation errors to investigate how selection acts on protein populations produced by amino acid misincorporations. We fitted the model to empirical observations of misincorporations obtained from over a hundred mass spectrometry datasets of E. coli and S. cerevisiae. We found that on average 20% to 23% of proteins synthesized in the cell are expected to harbor at least one amino acid misincorporation, and that deleterious misincorporations are less likely to occur. Combining misincorporation probabilities and the estimated fitness effects of amino acid substitutions in a population genetics framework, we found 74% of mistranslation events in E. coli and 94% in S. cerevisiae to be neutral. We further show that the set of available synonymous tRNAs is subject to evolutionary pressure, as the presence of missing tRNAs would increase codon-anticodon cross-reactivity and misincorporation error rates. Overall, we find that the translation machinery is likely optimal in E. coli and S. cerevisiae and that both local solutions at the level of codons and a global solution such as the tRNA pool can mitigate the impact of translation errors. We provide a framework to study the evolutionary impact of codon-specific translation errors and a method for their proteome-wide detection across organisms and conditions.
MeSH term(s)	Proteome/genetics ; Saccharomyces cerevisiae/genetics ; Protein Biosynthesis ; Escherichia coli/genetics ; Amino Acids/genetics ; RNA, Transfer/metabolism ; Codon/metabolism ; Mutation
Chemical Substances	Proteome ; Amino Acids ; RNA, Transfer (9014-25-9) ; Codon
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msae048
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 2137: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features.

Luppino, Federica / Adzhubei, Ivan A / Cassa, Christopher A / Toth-Petroczy, Agnes

Nature communications

2023 Volume 14, Issue 1, Page(s) 2230

Abstract: Despite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). ... ...

Abstract	Despite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) provide valuable evidence in variant assessment, but they are prone to misclassifying benign variants, contributing to false positives. Here, we develop Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for missense variants trained using extensive diagnostic data available in 59 actionable disease genes (American College of Medical Genetics and Genomics Secondary Findings v2.0, ACMG SF v2.0). DeMAG improves performance over existing VEPs by reaching balanced specificity (82%) and sensitivity (94%) on clinical data, and includes a novel epistatic feature, the 'partners score', which leverages evolutionary and structural partnerships of residues. The 'partners score' provides a general framework for modeling epistatic interactions, integrating both clinical and functional information. We provide our tool and predictions for all missense variants in 316 clinically actionable disease genes (demag.org) to facilitate the interpretation of variants and improve clinical decision-making.
MeSH term(s)	Humans ; United States ; Genomics/methods ; Mutation, Missense ; Genetic Variation ; Genetic Testing/methods
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37661-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Phenotypic mutations contribute to protein diversity and shape protein evolution.

Romero Romero, Maria Luisa / Landerer, Cedric / Poehls, Jonas / Toth-Petroczy, Agnes

Protein science : a publication of the Protein Society

2022 Volume 31, Issue 9, Page(s) e4397

Abstract: Errors in DNA replication generate genetic mutations, while errors in transcription and translation lead to phenotypic mutations. Phenotypic mutations are orders of magnitude more frequent than genetic ones, yet they are less understood. Here, we review ... ...

Abstract	Errors in DNA replication generate genetic mutations, while errors in transcription and translation lead to phenotypic mutations. Phenotypic mutations are orders of magnitude more frequent than genetic ones, yet they are less understood. Here, we review the types of phenotypic mutations, their quantifications, and their role in protein evolution and disease. The diversity generated by phenotypic mutation can facilitate adaptive evolution. Indeed, phenotypic mutations, such as ribosomal frameshift and stop codon readthrough, sometimes serve to regulate protein expression and function. Phenotypic mutations have often been linked to fitness decrease and diseases. Thus, understanding the protein heterogeneity and phenotypic diversity caused by phenotypic mutations will advance our understanding of protein evolution and have implications on human health and diseases.
MeSH term(s)	Codon, Terminator ; DNA Replication ; Evolution, Molecular ; Humans ; Mutation ; Protein Biosynthesis
Chemical Substances	Codon, Terminator
Language	English
Publishing date	2022-08-30
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4397
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 1: Show issues

Order via subito

Details ▾

Article ; Online: Adventures on the Routes of Protein Evolution-In Memoriam Dan Salah Tawfik (1955-2021).

Jackson, Colin / Toth-Petroczy, Agnes / Kolodny, Rachel / Hollfelder, Florian / Fuxreiter, Monika / Kamerlin, Shina Caroline Lynn / Tokuriki, Nobuhiko

Journal of molecular biology

2022 Volume 434, Issue 7, Page(s) 167462

Abstract: Understanding how proteins evolved not only resolves mysteries of the past, but also helps address challenges of the future, particularly those relating to the design and engineering of new protein functions. Here we review the work of Dan S. Tawfik, one ...

Abstract	Understanding how proteins evolved not only resolves mysteries of the past, but also helps address challenges of the future, particularly those relating to the design and engineering of new protein functions. Here we review the work of Dan S. Tawfik, one of the pioneers of this area, highlighting his seminal contributions in diverse fields such as protein design, high throughput screening, protein stability, fundamental enzyme-catalyzed reactions and promiscuity, that underpin biology and the origins of life. We discuss the influence of his work on how our models of enzyme and protein function have developed and how the main driving forces of molecular evolution were elucidated. The discovery of the rugged routes of evolution has enabled many practical applications, some which are now widely used.
MeSH term(s)	Catalysis ; Directed Molecular Evolution ; Enzymes ; Evolution, Molecular ; High-Throughput Screening Assays ; Proteins
Chemical Substances	Enzymes ; Proteins
Language	English
Publishing date	2022-01-29
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167462
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 867: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article ; Online: Hopeful (protein InDel) monsters?

Tóth-Petróczy, Agnes / Tawfik, Dan S

Structure (London, England : 1993)

2014 Volume 22, Issue 6, Page(s) 803–804

Abstract: In this issue of Structure, Arpino and colleagues describe in atomic detail how a protein stomachs a deletion within a helix, an event that rarely occurs in nature or in the lab. Can insertions and deletions (InDels) trigger dramatic structural ... ...

Abstract	In this issue of Structure, Arpino and colleagues describe in atomic detail how a protein stomachs a deletion within a helix, an event that rarely occurs in nature or in the lab. Can insertions and deletions (InDels) trigger dramatic structural transitions?
MeSH term(s)	Green Fluorescent Proteins/chemistry ; Green Fluorescent Proteins/genetics
Chemical Substances	enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2014-06-10
Publishing country	United States
Document type	Comment ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2014.05.013
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4141: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: The robustness and innovability of protein folds.

Tóth-Petróczy, Agnes / Tawfik, Dan S

Current opinion in structural biology

2014 Volume 26, Page(s) 131–138

Abstract: Assignment of protein folds to functions indicates that >60% of folds carry out one or two enzymatic functions, while few folds, for example, the TIM-barrel and Rossmann folds, exhibit hundreds. Are there structural features that make a fold amenable to ... ...

Abstract	Assignment of protein folds to functions indicates that >60% of folds carry out one or two enzymatic functions, while few folds, for example, the TIM-barrel and Rossmann folds, exhibit hundreds. Are there structural features that make a fold amenable to functional innovation (innovability)? Do these features relate to robustness--the ability to readily accumulate sequence changes? We discuss several hypotheses regarding the relationship between the architecture of a protein and its evolutionary potential. We describe how, in a seemingly paradoxical manner, opposite properties, such as high stability and rigidity versus conformational plasticity and structural order versus disorder, promote robustness and/or innovability. We hypothesize that polarity--differentiation and low connectivity between a protein's scaffold and its active-site--is a key prerequisite for innovability.
MeSH term(s)	Catalytic Domain ; Evolution, Molecular ; Proteins/chemistry ; Proteins/metabolism
Chemical Substances	Proteins
Keywords	covid19
Language	English
Publishing date	2014-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2014.06.007
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 3206: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: CD-CODE: crowdsourcing condensate database and encyclopedia.

Rostam, Nadia / Ghosh, Soumyadeep / Chow, Chi Fung Willis / Hadarovich, Anna / Landerer, Cedric / Ghosh, Rajat / Moon, HongKee / Hersemann, Lena / Mitrea, Diana M / Klein, Isaac A / Hyman, Anthony A / Toth-Petroczy, Agnes

Nature methods

2023 Volume 20, Issue 5, Page(s) 673–676

Abstract: The discovery of biomolecular condensates transformed our understanding of intracellular compartmentalization of molecules. To integrate interdisciplinary scientific knowledge about the function and composition of biomolecular condensates, we developed ... ...

Abstract	The discovery of biomolecular condensates transformed our understanding of intracellular compartmentalization of molecules. To integrate interdisciplinary scientific knowledge about the function and composition of biomolecular condensates, we developed the crowdsourcing condensate database and encyclopedia ( cd-code.org ). CD-CODE is a community-editable platform, which includes a database of biomolecular condensates based on the literature, an encyclopedia of relevant scientific terms and a crowdsourcing web application. Our platform will accelerate the discovery and validation of biomolecular condensates, and facilitate efforts to understand their role in disease and as therapeutic targets.
MeSH term(s)	Crowdsourcing ; Databases, Factual ; Software
Language	English
Publishing date	2023-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-023-01831-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 6022: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Systematic Mapping of Protein Mutational Space by Prolonged Drift Reveals the Deleterious Effects of Seemingly Neutral Mutations.

Rockah-Shmuel, Liat / Tóth-Petróczy, Ágnes / Tawfik, Dan S

PLoS computational biology

2015 Volume 11, Issue 8, Page(s) e1004421

Abstract: Systematic mappings of the effects of protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins are tolerant to most amino acid substitutions, including substitutions in positions that are highly ... ...

Abstract	Systematic mappings of the effects of protein mutations are becoming increasingly popular. Unexpectedly, these experiments often find that proteins are tolerant to most amino acid substitutions, including substitutions in positions that are highly conserved in nature. To obtain a more realistic distribution of the effects of protein mutations, we applied a laboratory drift comprising 17 rounds of random mutagenesis and selection of M.HaeIII, a DNA methyltransferase. During this drift, multiple mutations gradually accumulated. Deep sequencing of the drifted gene ensembles allowed determination of the relative effects of all possible single nucleotide mutations. Despite being averaged across many different genetic backgrounds, about 67% of all nonsynonymous, missense mutations were evidently deleterious, and an additional 16% were likely to be deleterious. In the early generations, the frequency of most deleterious mutations remained high. However, by the 17th generation, their frequency was consistently reduced, and those remaining were accepted alongside compensatory mutations. The tolerance to mutations measured in this laboratory drift correlated with sequence exchanges seen in M.HaeIII's natural orthologs. The biophysical constraints dictating purging in nature and in this laboratory drift also seemed to overlap. Our experiment therefore provides an improved method for measuring the effects of protein mutations that more closely replicates the natural evolutionary forces, and thereby a more realistic view of the mutational space of proteins.
MeSH term(s)	Bacterial Proteins/genetics ; Computational Biology/methods ; DNA Modification Methylases/genetics ; Evolution, Molecular ; Genetic Drift ; Haemophilus/genetics ; Models, Genetic ; Mutation/genetics ; Mutation/physiology ; Proteins/genetics
Chemical Substances	Bacterial Proteins ; Proteins ; DNA Modification Methylases (EC 2.1.1.-)
Language	English
Publishing date	2015-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1004421
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Protein insertions and deletions enabled by neutral roaming in sequence space.

Tóth-Petróczy, Agnes / Tawfik, Dan S

Molecular biology and evolution

2013 Volume 30, Issue 4, Page(s) 761–771

Abstract: Backbone modifications via insertions and deletions (InDels) may exert dramatic effects, for better (mediating new functions) and for worse (causing loss of structure and/or function). However, contrary to point mutations (substitutions), our knowledge ... ...

Abstract	Backbone modifications via insertions and deletions (InDels) may exert dramatic effects, for better (mediating new functions) and for worse (causing loss of structure and/or function). However, contrary to point mutations (substitutions), our knowledge of the evolution and structural-functional effects of InDels is limited and so is our capability to engineer them. We sought to assess how deleterious InDels are relative to point mutations and understand the mechanisms that mediate their acceptance. Analysis of the evolution of InDels in orthologous protein phylogenies indicated that their rate of purging is 9- to 100-fold higher than for point mutations. In yeast, for example, the substitutions-to-InDels ratio is approximately 14-fold higher in protein coding than in noncoding regions. The incorporation of InDels relative to substitutions is not only slow but also nonlinear. On average, ≥50 substitutions accumulate before the appearance of the first InDel. We also found enriched substitutions in sequential and spatial proximity to InDels, suggesting that certain substitutions are correlated with InDels. As indicated by the lag in InDels accumulation, some of these correlated substitutions may have occurred first, as apparently neutral mutations, and later enabled the accumulation of InDels that would be otherwise purged. Thus, compensatory substitutions may follow InDels in an "adaptive walk" as traditionally assumed, but might also accumulate first, by "neutral roaming." The dynamics of InDels accumulation also depends on their genomic frequencies-InDels in flies are 4-fold more frequent than in yeast and tend to be compensated rather than enabled.
MeSH term(s)	Animals ; DNA, Fungal/genetics ; DNA, Intergenic/genetics ; Drosophila/genetics ; Evolution, Molecular ; Fungi/genetics ; Genes, Insect ; INDEL Mutation ; Models, Genetic ; Phylogeny ; Point Mutation ; Saccharomyces cerevisiae/genetics ; Sequence Analysis, DNA
Chemical Substances	DNA, Fungal ; DNA, Intergenic
Language	English
Publishing date	2013-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/mst003
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 2137: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

Article: Adventures on the Routes of Protein Evolution—In Memoriam Dan Salah Tawfik (1955–2021)

Jackson, Colin / Toth-Petroczy, Agnes / Kolodny, Rachel / Hollfelder, Florian / Fuxreiter, Monika / Kamerlin, Shina Caroline Lynn / Tokuriki, Nobuhiko

Journal of molecular biology. 2022 Apr. 15, v. 434, no. 7

2022

Abstract	Understanding how proteins evolved not only resolves mysteries of the past, but also helps address challenges of the future, particularly those relating to the design and engineering of new protein functions. Here we review the work of Dan S. Tawfik, one of the pioneers of this area, highlighting his seminal contributions in diverse fields such as protein design, high throughput screening, protein stability, fundamental enzyme-catalyzed reactions and promiscuity, that underpin biology and the origins of life. We discuss the influence of his work on how our models of enzyme and protein function have developed and how the main driving forces of molecular evolution were elucidated. The discovery of the rugged routes of evolution has enabled many practical applications, some which are now widely used.
Keywords	enzymes ; evolution ; molecular biology
Language	English
Dates of publication	2022-0415
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167462
Database	NAL-Catalogue (AGRICOLA)

In stock of ZB MED Bonn / Germany

Z 4' 63/108: Show issues

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Details ▾
- See ZB MED holdings
- Order with fees

To top

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Bonn / Germany

Order via subito

Inter-library loan at ZB MED