Molecular origins of folding rate differences in the thioredoxin family

2020 ◽  
Vol 477 (6) ◽  
pp. 1083-1087 ◽  
Author(s):  
Athi N. Naganathan
Keyword(s):  
Protein Design ◽  
Redox Balance ◽  
Model Systems ◽  
Sequence Evolution ◽  
Specific Sequence ◽  
Folding Rate ◽  
Folding Rates ◽  
Reconstruction Methods ◽  
Sequence Reconstruction ◽  
Selected Subset

Thioredoxins are a family of conserved oxidoreductases responsible for maintaining redox balance within cells. They have also served as excellent model systems for protein design and engineering studies particularly through ancestral sequence reconstruction methods. The recent work by Gamiz-Arco et al. [Biochem J (2019) 476, 3631–3647] answers fundamental questions on how specific sequence differences can contribute to differences in folding rates between modern and ancient thioredoxins but also among a selected subset of modern thioredoxins. They surprisingly find that rapid unassisted folding, a feature of ancient thioredoxins, is not conserved in the modern descendants suggestive of co-evolution of better folding machinery that likely enabled the accumulation of mutations that slow-down folding. The work thus provides an interesting take on the expected folding-stability-function constraint while arguing for additional factors that contribute to sequence evolution and hence impact folding efficiency.

An Effective Cumulative Torsion Angles Model for Prediction of Protein Folding Rates

2020 ◽  
Vol 27 (4) ◽  
pp. 321-328 ◽  
Author(s):  
Yanru Li ◽  
Ying Zhang ◽  
Jun Lv
Keyword(s):  
Protein Folding ◽  
Size Structure ◽  
Conformational Space ◽  
Coefficient Of Determination ◽  
Folding Rate ◽  
Torsion Angles ◽  
Folding Rates ◽  
Protein Folding Rate ◽  
Optimal Set ◽  
Conformation Space

Background: Protein folding rate is mainly determined by the size of the conformational space to search, which in turn is dictated by factors such as size, structure and amino-acid sequence in a protein. It is important to integrate these factors effectively to form a more precisely description of conformation space. But there is no general paradigm to answer this question except some intuitions and empirical rules. Therefore, at the present stage, predictions of the folding rate can be improved through finding new factors, and some insights are given to the above question. Objective: Its purpose is to propose a new parameter that can describe the size of the conformational space to improve the prediction accuracy of protein folding rate. Method: Based on the optimal set of amino acids in a protein, an effective cumulative backbone torsion angles (CBTAeff) was proposed to describe the size of the conformational space. Linear regression model was used to predict protein folding rate with CBTAeff as a parameter. The degree of correlation was described by the coefficient of determination and the mean absolute error MAE between the predicted folding rates and experimental observations. Results: It achieved a high correlation (with the coefficient of determination of 0.70 and MAE of 1.88) between the logarithm of folding rates and the (CBTAeff)0.5 with experimental over 112 twoand multi-state folding proteins. Conclusion: The remarkable performance of our simplistic model demonstrates that CBTA based on optimal set was the major determinants of the conformation space of natural proteins.

The Influences of Palindromes in mRNA on Protein Folding Rates

2020 ◽  
Vol 27 (4) ◽  
pp. 303-312 ◽  
Author(s):  
Ruifang Li ◽  
Hong Li ◽  
Sarula Yang ◽  
Xue Feng
Keyword(s):  
Protein Folding ◽  
Regression Analysis ◽  
Linear Regression ◽  
Linear Regression Analysis ◽  
Folding Rate ◽  
Folding Rates ◽  
Negative Linear Correlation ◽  
Protein Folding Rate ◽  
The Relationship ◽  
Structure Environment

Background: It is currently believed that protein folding rates are influenced by protein structure, environment and temperature, amino acid sequence and so on. We have been working for long to determine whether and in what ways mRNA affects the protein folding rate. A large number of palindromes aroused our attention in our previous research. Whether these palindromes do have important influences on protein folding rates and what’s the mechanism? Very few related studies are focused on these problems. Objective: In this article, our motivation is to find out if palindromes have important influences on protein folding rates and what’s the mechanism. Method: In this article, the parameters of the palindromes were defined and calculated, the linear regression analysis between the values of each parameter and the experimental protein folding rates were done. Furthermore, to compare the results of different kinds of proteins, proteins were classified into the two-state proteins and the multi-state proteins. For the two kinds of proteins, the above linear regression analysis were performed respectively. Results : Protein folding rates were negatively correlated to the palindrome frequencies for all proteins. An extremely significant negative linear correlation appeared in the relationship between palindrome densities and protein folding rates. And the repeatedly used bases by different palindromes simultaneously have an important effect on the relationship between palindrome density and protein folding rate. Conclusion: The palindromes have important influences on protein folding rates, and the repeatedly used bases in different palindromes simultaneously play a key role in influencing the protein folding rates.

scholarly journals Retardation of folding rates of substrate proteins in the nanocage of GroEL

2020 ◽  
Author(s):  
Eda Koculi ◽  
D. Thirumalai
Keyword(s):  
Short Duration ◽  
Time Scale ◽  
Folding Rate ◽  
E Coli ◽  
Biological Time ◽  
Folding Rates ◽  
Substrate Proteins ◽  
Do So

AbstractThe E. Coli. ATP-consuming chaperonin machinery, a complex between GroEL and GroES, has evolved to facilitate folding of substrate proteins (SPs) that cannot do so spontaneously. A series of kinetic experiments show that the SPs are encapsulated in the GroEL/ES nano cage for a short duration. If confining the SPs in the predominantly polar cage of GroEL in order to help folding, the assisted folding rate, relative to the bulk value, should always be enhanced. Here, we show that this is not the case for the folding of rhodanese in the presence of the full machinery of GroEL/ES and ATP. The assisted folding rate of rhodanese decreases. Based on our finding and those reported in other studies, we suggest that the ATP-consuming chaperonin machinery has evolved to optimize the product of the folding rate and the yield of the folded SPs on the biological time scale. Neither the rate nor the yield is separately maximized.

scholarly journals An Integrated Model of Phenotypic Trait Changes and Site-Specific Sequence Evolution

2017 ◽  
Vol 66 (6) ◽  
pp. 917-933 ◽  
Author(s):  
Eli Levy Karin ◽  
Susann Wicke ◽  
Tal Pupko ◽  
Itay Mayrose
Keyword(s):  
Integrated Model ◽  
Phenotypic Trait ◽  
Sequence Evolution ◽  
Specific Sequence ◽  
Site Specific

scholarly journals Study on the Influence of mRNA, the Genetic Language, on Protein Folding Rates

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruifang Li ◽  
Hong Li ◽  
Xue Feng ◽  
Ruifeng Zhao ◽  
Yongxia Cheng
Keyword(s):  
Protein Folding ◽  
Amino Acid ◽  
Protein Structures ◽  
Gc Content ◽  
Amino Acid Sequences ◽  
Information Redundancy ◽  
Folding Rate ◽  
Folding Rates ◽  
Related Information ◽  
Linear Regressions

Many works have reported that protein folding rates are influenced by the characteristics of amino acid sequences and protein structures. However, few reports on the problem of whether the corresponding mRNA sequences are related to the protein folding rates can be found. An mRNA sequence is regarded as a kind of genetic language, and its vocabulary and phraseology must provide influential information regarding the protein folding rate. In the present work, linear regressions on the parameters of the vocabulary and phraseology of mRNA sequences and the corresponding protein folding rates were analyzed. The results indicated that D2 (the adjacent base-related information redundancy) values and the GC content values of the corresponding mRNA sequences exhibit significant negative relations with the protein folding rates, but D1 (the single base information redundancy) values exhibit significant positive relations with the protein folding rates. In addition, the results show that the relationships between the parameters of the genetic language and the corresponding protein folding rates are obviously different for different protein groups. Some useful parameters that are related to protein folding rates were found. The results indicate that when predicting protein folding rates, the information from protein structures and their amino acid sequences is insufficient, and some information for regulating the protein folding rates must be derived from the mRNA sequences.

scholarly journals Alignment-Integrated Reconstruction of Ancestral Sequences Improves Accuracy

2020 ◽  
Vol 12 (9) ◽  
pp. 1549-1565
Author(s):  
Kelsey Aadland ◽  
Bryan Kolaczkowski
Keyword(s):  
Sequence Alignment ◽  
Evolutionary Process ◽  
Sequence Evolution ◽  
Sequence Alignments ◽  
Ancestral Sequences ◽  
Structural And Functional Properties ◽  
Sequence Reconstruction ◽  
Alignment Errors ◽  
The Impact ◽  
Alignment Uncertainty

Abstract Ancestral sequence reconstruction (ASR) uses an alignment of extant protein sequences, a phylogeny describing the history of the protein family and a model of the molecular-evolutionary process to infer the sequences of ancient proteins, allowing researchers to directly investigate the impact of sequence evolution on protein structure and function. Like all statistical inferences, ASR can be sensitive to violations of its underlying assumptions. Previous studies have shown that, whereas phylogenetic uncertainty has only a very weak impact on ASR accuracy, uncertainty in the protein sequence alignment can more strongly affect inferred ancestral sequences. Here, we show that errors in sequence alignment can produce errors in ASR across a range of realistic and simplified evolutionary scenarios. Importantly, sequence reconstruction errors can lead to errors in estimates of structural and functional properties of ancestral proteins, potentially undermining the reliability of analyses relying on ASR. We introduce an alignment-integrated ASR approach that combines information from many different sequence alignments. We show that integrating alignment uncertainty improves ASR accuracy and the accuracy of downstream structural and functional inferences, often performing as well as highly accurate structure-guided alignment. Given the growing evidence that sequence alignment errors can impact the reliability of ASR studies, we recommend that future studies incorporate approaches to mitigate the impact of alignment uncertainty. Probabilistic modeling of insertion and deletion events has the potential to radically improve ASR accuracy when the model reflects the true underlying evolutionary history, but further studies are required to thoroughly evaluate the reliability of these approaches under realistic conditions.

scholarly journals The lack of rhodanese RhdA affects the sensitivity of Azotobacter vinelandii to oxidative events

2009 ◽  
Vol 418 (1) ◽  
pp. 135-143 ◽  
Author(s):  
Angelo Cereda ◽  
Aristodemo Carpen ◽  
Gianluca Picariello ◽  
Gabriella Tedeschi ◽  
Silvia Pagani
Keyword(s):  
Oxidative Damage ◽  
Active Site ◽  
Azotobacter Vinelandii ◽  
Redox Balance ◽  
Growth Conditions ◽  
Model Systems ◽  
Phenotypic Characterization

The rhdA gene of Azotobacter vinelandii codes for RhdA, a rhodanese-domain protein with an active-site loop structure which has not currently been found in proteins of the rhodanese-homology superfamily. Considering the lack of information on the functional role of the ubiquitous rhodaneses, in the present study we examined the in vivo functions of RhdA by using an A. vinelandii mutant strain (MV474), in which the rhdA gene was disrupted by deletion. Preliminary phenotypic characterization of the rhdA mutant suggested that RhdA could exert protection over Fe–S enzymes, which are easy targets for oxidative damage. To highlight the role of RhdA in preserving sensitive Fe–S clusters, in the present study we analysed the defects of the rhdA-null strain by exploiting growth conditions which resulted in enhancing the catalytic deficiency of enzymes with vulnerable Fe–S clusters. We found that a lack of RhdA impaired A. vinelandii growth in the presence of gluconate, a carbon source that activates the Entner–Doudoroff pathway in which the first enzyme, 6-phosphogluconate dehydratase, employs a 4Fe–4S cluster as an active-site catalyst. By combining proteomics, enzymatic profiles and model systems to generate oxidative stress, evidence is provided that to rescue the effects of a lack of RhdA, A. vinelandii needed to activate defensive activities against oxidative damage. The possible functionality of RhdA as a redox switch which helps A. vinelandii in maintaining the cellular redox balance was investigated by using an in vitro model system that demonstrated reversible chemical modifications in the highly reactive RhdA Cys230 thiol.

Capturing protein folding-relevant topology via absolute contact order variants

2014 ◽  
Vol 13 (01) ◽  
pp. 1450005 ◽  
Author(s):  
Amy S. Wagaman ◽  
Sheila S. Jaswal
Keyword(s):  
Protein Folding ◽  
Heavy Atom ◽  
Folding Rate ◽  
Data Set ◽  
Structural Class ◽  
Protein Structural Class ◽  
Folding Rates ◽  
Contact Order ◽  
Energetic Interactions ◽  
Structural Classes

Absolute contact order is one of the simplest parameters used to predict protein folding rates. Many variants of contact order (CO) have been applied to highlight different aspects of contact neighborhoods and their relationship to folding. However, a systematic study of the influence of CO variants on correlation with folding rate has not been performed for a large combined set of multi- and two-state proteins. We explore different contact neighborhoods and resulting CO by varying the distance thresholds and weighting of sequence separation for heavy atom and residue-based counting methods for a set of 136 proteins diverse across folding and structural classes. We examine the changes in contact neighborhoods and compare correlations with our CO variants and the protein folding rates across our data set as well as by folding type and structural class. Different CO variants lead to the strongest correlations within each protein structural class. Our results demonstrate that backbone topology at a distance beyond where energetic interactions dominate is able to capture folding determinants, and suggest that more sensitive methods of characterizing contact relationships may improve ln kf prediction for diverse protein sets.

scholarly journals Mechanisms of Hop Inhibition Include the Transmembrane Redox Reaction

2009 ◽  
Vol 76 (1) ◽  
pp. 142-149 ◽  
Author(s):  
Jürgen Behr ◽  
Rudi F. Vogel
Keyword(s):  
Oxidative Stress ◽  
Cyclic Voltammetry ◽  
Stress Responses ◽  
Redox Reaction ◽  
Mechanistic Model ◽  
Ion Homeostasis ◽  
Lactobacillus Brevis ◽  
Redox Balance ◽  
Resistance Mechanisms ◽  
Model Systems

ABSTRACT In this work, a novel mechanistic model of hop inhibition beyond the proton ionophore action toward (beer spoiling) bacteria was developed. Investigations were performed with model systems using cyclic voltammetry for the determination of redox processes/conditions in connection with growth challenges with hop-sensitive and -resistant Lactobacillus brevis strains in the presence of oxidants. Cyclic voltammetry identified a transmembrane redox reaction of hop compounds at low pH (common in beer) and in the presence of manganese (present in millimolar levels in lactic acid bacteria). The antibacterial action of hop compounds could be extended from the described proton ionophore activity, lowering the intracellular pH, to pronounced redox reactivity, causing cellular oxidative damage. Accordingly, a correlation between the resistance of L. brevis strains to a sole oxidant to their resistance to hop could not be expected and was not detected. However, in connection with our recent study concerning hop ionophore properties and the resistance of hop-sensitive and -tolerant L. brevis strains toward proton ionophores (J. Behr and R. F. Vogel, J. Agric. Food Chem. 57:6074-6081, 2009), we suggest that both ionophore and oxidant resistance are required for survival under hop stress conditions and confirmed this correlation according to the novel mechanistic model. In consequence, the expression of several published hop resistance mechanisms involved in manganese binding/transport and intracellular redox balance, as well as that of proteins involved in oxidative stress under “highly reducing” conditions (cf. anaerobic cultivation and “antioxidative” hop compounds in the growth medium), is now comprehensible. Accordingly, hop resistance as a multifactorial dynamic property at least implies distinct resistance levels against two different mechanisms of hop inhibition, namely, proton ionophore-induced and oxidative stress-induced mechanisms. Beyond this specific model of hop inhibition, these investigations provide general insight on the role of electrophysiology and ion homeostasis in bacterial stress responses to membrane-active drugs.

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