scholarly journals Effect of protein structure on evolution of cotranslational folding

2020 ◽  
Author(s):  
V. Zhao ◽  
W. M. Jacobs ◽  
E. I. Shakhnovich
Keyword(s):  
Protein Structures ◽  
Evolutionary Model ◽  
Translation Speed ◽  
Folding Intermediates ◽  
Synonymous Mutations ◽  
Rare Codons ◽  
Contact Order ◽  
Local Contact ◽  
Cotranslational Folding ◽  
Lower Contact

AbstractCotranslational folding is expected to occur when the folding speed of the nascent chain is faster than the translation speed of the ribosome, but it is difficult to predict which proteins cotranslationally fold. Here, we simulate evolution of model proteins to investigate how native structure influences evolution of cotranslational folding. We developed a model that connects protein folding during and after translation to cellular fitness. Model proteins evolved improved folding speed and stability, with proteins adopting one of two strategies for folding quickly. Low contact order proteins evolve to fold cotranslationally. Such proteins adopt native conformations early on during the translation process, with each subsequently translated residue establishing additional native contacts. On the other hand, high contact order proteins tend not to be stable in their native conformations until the full chain is nearly extruded. We also simulated evolution of slowly translating codons, finding that slowing translation at certain positions enhances cotranslational folding. Finally, we investigated real protein structures using a previously published dataset that identified evolutionarily conserved rare codons in E. coli genes and associated such codons with cotranslational folding intermediates. We found that protein substructures preceding conserved rare codons tend to have lower contact orders, in line with our finding that lower contact order proteins are more likely to fold cotranslationally. Our work shows how evolutionary selection pressure can cause proteins with local contact topologies to evolve cotranslational folding.Statement of significanceSubstantial evidence exists for proteins folding as they are translated by the ribosome. Here we developed a biologically intuitive evolutionary model to show that avoiding premature protein degradation can be a sufficient evolutionary force to drive evolution of cotranslational folding. Furthermore, we find that whether a protein’s native fold consists of more local or more nonlocal contacts affects whether cotranslational folding evolves. Proteins with local contact topologies are more likely to evolve cotranslational folding through nonsynonymous mutations that strengthen native contacts as well as through synonymous mutations that provide sufficient time for cotranslational folding intermediates to form.

scholarly journals Genome Variability and Capsid Structural Constraints of Hepatitis A Virus

2003 ◽  
Vol 77 (1) ◽  
pp. 452-459 ◽  
Author(s):  
Glòria Sánchez ◽  
Albert Bosch ◽  
Rosa M. Pintó
Keyword(s):  
Codon Usage ◽  
Rna Structure ◽  
Hepatitis A ◽  
Hepatitis A Virus ◽  
Foot And Mouth Disease ◽  
Structural Constraints ◽  
Translation Speed ◽  
Synonymous Mutations ◽  
Rare Codons ◽  
Mouth Disease Virus

ABSTRACT The number of synonymous mutations per synonymous site (Ks ), the number of nonsynonymous mutations per nonsynonymous site (Ka ), and the codon usage statistic (Nc ) were calculated for several hepatitis A virus (HAV) isolates. While Ks was similar to those of poliovirus (PV) and foot-and-mouth disease virus (FMDV), Ka was 1 order of magnitude lower. The Nc parameter provides information on codon usage bias and decreases when bias increases. The Nc value in HAV was about 38, while in PV and FMDV, it was about 53. The emergence of 22 rare codons in front of 8 in PV and 7 in FMDV was detected. Most of the conserved rare codons of the P1 region were strategically located at the carboxy borders of β barrels and α helices, their potential function being the assurance of proper folding of the capsid proteins through a decrease in the translation speed. This strategic location was not observed for amino acids encoded by the conserved rare codons of the 3D region. The percentage of bases with low pairing number values was higher in the latter region, suggesting a role of the conserved rare codons in the maintenance of RNA structure. Many of the rare codons in HAV are among the most frequent in humans, unlike in PV or in FMDV. This fact may be explained by the lack of cellular shutoff in HAV. One hypothesis is that HAV has evolved in order to avoid competition with its host for cellular tRNAs.

scholarly journals Systematic mapping of free energy landscapes of a growing filamin domain during biosynthesis

2018 ◽  
Vol 115 (39) ◽  
pp. 9744-9749 ◽  
Author(s):  
Christopher A. Waudby ◽  
Tomasz Wlodarski ◽  
Maria-Evangelia Karyadi ◽  
Anaïs M. E. Cassaignau ◽  
Sammy H. S. Chan ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Biosynthesis ◽  
Energy Landscapes ◽  
Native Structure ◽  
Folding Intermediates ◽  
Cotranslational Folding ◽  
Partially Folded Intermediate ◽  
Free Energy Landscapes ◽  
Peptidyl Prolyl Isomerases ◽  
Structural Characterizations

Cotranslational folding (CTF) is a fundamental molecular process that ensures efficient protein biosynthesis and minimizes the formation of misfolded states. However, the complexity of this process makes it extremely challenging to obtain structural characterizations of CTF pathways. Here, we correlate observations of translationally arrested nascent chains with those of a systematic C-terminal truncation strategy. We create a detailed description of chain length-dependent free energy landscapes associated with folding of the FLN5 filamin domain, in isolation and on the ribosome, and thus, quantify a substantial destabilization of the native structure on the ribosome. We identify and characterize two folding intermediates formed in isolation, including a partially folded intermediate associated with the isomerization of a conserved cis proline residue. The slow folding associated with this process raises the prospect that neighboring unfolded domains might accumulate and misfold during biosynthesis. We develop a simple model to quantify the risk of misfolding in this situation and show that catalysis of folding by peptidyl-prolyl isomerases is sufficient to eliminate this hazard.

scholarly journals Cotranslational folding allows misfolding-prone proteins to circumvent deep kinetic traps

2020 ◽  
Vol 117 (3) ◽  
pp. 1485-1495 ◽  
Author(s):  
Amir Bitran ◽  
William M. Jacobs ◽  
Xiadi Zhai ◽  
Eugene Shakhnovich
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Folding Kinetics ◽  
Rare Codons ◽  
Cotranslational Folding ◽  
Nascent Chain ◽  
Kinetic Traps ◽  
Optimal Window

Many large proteins suffer from slow or inefficient folding in vitro. It has long been known that this problem can be alleviated in vivo if proteins start folding cotranslationally. However, the molecular mechanisms underlying this improvement have not been well established. To address this question, we use an all-atom simulation-based algorithm to compute the folding properties of various large protein domains as a function of nascent chain length. We find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by nonnative interactions involving C-terminal residues. Thus, cotranslational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins’ sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modeling, we show that under certain conditions, such a slowdown indeed improves cotranslational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from cotranslational folding due to a lack of significant nonnative interactions, and indeed these proteins’ sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell and how biomolecular self-assembly may be optimized evolutionarily.

Mimicking cotranslational folding of prosubtilisin E in vitro

2020 ◽  
Vol 167 (5) ◽  
pp. 473-482 ◽  
Author(s):  
Sung-Gun Kim ◽  
Yu-Jen Chen ◽  
Liliana Falzon ◽  
Jean Baum ◽  
Masayori Inouye
Keyword(s):  
Crucial Role ◽  
Tertiary Structure ◽  
Molten Globule ◽  
Secondary Structures ◽  
Terminal Region ◽  
Folding Intermediates ◽  
C Terminus ◽  
Cotranslational Folding ◽  
N Terminus

Abstract Nascent polypeptides are synthesized on ribosomes starting at the N-terminus and simultaneously begin to fold during translation. We constructed N-terminal fragments of prosubtilisin E containing an intramolecular chaperone (IMC) at N-terminus to mimic cotranslational folding intermediates of prosubtilisin. The IMC-fragments of prosubtilisin exhibited progressive enhancement of their secondary structures and thermostabilities with increasing polypeptide length. However, even the largest IMC-fragment with 72 residues truncated from the C-terminus behaved as a molten globule, indicating the requirement of the C-terminal region to have a stable tertiary structure. Furthermore, truncation of the IMC in the IMC-fragments resulted in aggregation, suggesting that the IMC plays a crucial role to prevent misfolding and aggregation of cotranslational folding intermediates during translation of prosubtilisin polypeptide.

scholarly journals Globally Defining the Effects of Amino Acid Mutations across a Picornavirus Capsid

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 111
Author(s):  
Florian Mattenberger ◽  
Ron Geller
Keyword(s):  
Amino Acid ◽  
Rna Viruses ◽  
Large Fraction ◽  
Protein Structures ◽  
Single Amino Acid ◽  
Relative Fitness ◽  
Mutation Rates ◽  
Phenotypic Data ◽  
Synonymous Mutations ◽  
Amino Acid Mutations

RNA viruses are characterized by their extreme mutation rates, which play key roles in their biology and give them the ability to rapidly adapt to new environments. However, non-synonymous mutations tend to be largely deleterious to protein function, raising the question of how the proteins of RNA viruses maintain functionality in the face of high mutation rates. This is of particular relevance to the capsids of non-enveloped RNA viruses, which form highly complex protein structures that assemble from numerous subunits, interact with cellular host factors to mediate entry and uncoating, and are under strong immune selection. To better understand how viral capsids accommodate mutations, we generated viral populations harboring a large fraction of all possible single amino acid mutations in a picornavirus capsid. We then used high-fidelity next-generation sequencing to derive the relative fitness of these mutations compared to the wildtype sequence. Combining our results with available structural, genetic, and phenotypic data, we are able to provide a comprehensive understanding of the ability of a viral capsid to accommodate mutations.

scholarly journals Synonymous but not Silent: The Codon Usage Code for Gene Expression and Protein Folding

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
Yi Liu ◽  
Qian Yang ◽  
Fangzhou Zhao
Keyword(s):  
Gene Expression ◽  
Protein Folding ◽  
Codon Usage ◽  
Protein Structures ◽  
Large Body ◽  
Annual Review ◽  
Publication Date ◽  
Translation Efficiency ◽  
Mrna Levels ◽  
Synonymous Mutations

Codon usage bias, the preference for certain synonymous codons, is found in all genomes. Although synonymous mutations were previously thought to be silent, a large body of evidence has demonstrated that codon usage can play major roles in determining gene expression levels and protein structures. Codon usage influences translation elongation speed and regulates translation efficiency and accuracy. Adaptation of codon usage to tRNA expression determines the proteome landscape. In addition, codon usage biases result in nonuniform ribosome decoding rates on mRNAs, which in turn influence the cotranslational protein folding process that is critical for protein function in diverse biological processes. Conserved genome-wide correlations have also been found between codon usage and protein structures. Furthermore, codon usage is a major determinant of mRNA levels through translation-dependent effects on mRNA decay and translation-independent effects on transcriptional and posttranscriptional processes. Here, we discuss the multifaceted roles and mechanisms of codon usage in different gene regulatory processes. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Evolutionary model of protein secondary structure capable of revealing new biological relationships

2019 ◽  
Author(s):  
Jhih-Siang Lai ◽  
Burkhard Rost ◽  
Bostjan Kobe ◽  
Mikael Bodén
Keyword(s):  
Amino Acid ◽  
Secondary Structure ◽  
Predictive Accuracy ◽  
Protein Structures ◽  
Protein Secondary Structure ◽  
Evolutionary Model ◽  
Ancestral Sequences ◽  
Recent Success ◽  
Protein Functions ◽  
Sequence Reconstruction

AbstractAncestral sequence reconstruction has had recent success in decoding the origins and the determinants of complex protein functions. However, phylo­genetic analyses of remote homologues must handle extreme amino-acid se­quence diversity resulting from extended periods of evolutionary change. We exploited the wealth of protein structures to develop an evolutionary model based on protein secondary structure. The approach follows the differences between discrete secondary structure states observed in modern proteins and those hypothesised in their immediate ancestors. We implemented maximum likelihood-based phylogenetic inference to reconstruct ancestral secondary structure. The predictive accuracy from the use of the evolutionary model surpasses that of comparative modelling and sequence-based prediction; the reconstruction extracts information not available from modern structures or the ancestral sequences alone. Based on a phylogenetic analysis of multiple protein families, we showed that the model can highlight relationships that are evolutionarily rooted in structure and not evident in amino acid-based analysis.

scholarly journals Whole-Genome Sequences of the Severe Acute Respiratory Syndrome Coronavirus-2 obtained from Romanian patients between March and June of 2020

2020 ◽  
Author(s):  
Mihaela Lazar ◽  
Odette Popovici ◽  
Barbara Mühlemann ◽  
Tim Durfee ◽  
Razvan Stan
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Protein Stability ◽  
Treatment Options ◽  
Protein Structures ◽  
Spike Glycoprotein ◽  
Effective Prevention ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Genomes ◽  
Synonymous Mutations

AbstractImpact of mutations on the evolution of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) are needed for ongoing global efforts to track and trace the current pandemic, in order to enact effective prevention and treatment options. SARS-Co-V-2 viral genomes were detected and sequenced from 18 Romanian patients suffering from coronavirus disease-2019. Viral Spike S glycoprotein sequences were used to generate model structures and assess the role of mutations on protein stability. We integrated the phylogenetic tree within the available European SARS-Co-V-2 genomic sequences. We further provide an epidemiological overview of the pre-existing conditions that are lethal in relevant Romanian patients. Non-synonymous mutations in the viral Spike glycoprotein relating to infectivity are constructed in models of protein structures. Continuing search to limit and treat SARS-CoV-2 benefit from our contribution in delineating the viral Spike glycoprotein mutations, as well as from assessment of their role on protein stability or complex formation with human receptor angiotensin-converting enzyme 2. Our results help implement and extend worldwide genomic surveillance of coronavirus disease-2019.

scholarly journals Learning structural bioinformatics and evolution with a snake puzzle

2016 ◽  
Vol 2 ◽  
pp. e100 ◽  
Author(s):  
Gonzalo S. Nido ◽  
Ludovica Bachschmid-Romano ◽  
Ugo Bastolla ◽  
Alberto Pascual-García
Keyword(s):  
Teaching Practice ◽  
Protein Structures ◽  
Simple Algorithm ◽  
Structural Bioinformatics ◽  
Data Availability ◽  
Folding Kinetics ◽  
Contact Order ◽  
Contact Matrix ◽  
Supplementary Material ◽  
High Level

We propose here a working unit for teaching basic concepts of structural bioinformatics and evolution through the example of a wooden snake puzzle, strikingly similar to toy models widely used in the literature of protein folding. In our experience, developed at a Master’s course at the Universidad Autónoma de Madrid (Spain), the concreteness of this example helps to overcome difficulties caused by the interdisciplinary nature of this field and its high level of abstraction, in particular for students coming from traditional disciplines. The puzzle will allow us discussing a simple algorithm for finding folded solutions, through which we will introduce the concept of the configuration space and the contact matrix representation. This is a central tool for comparing protein structures, for studying simple models of protein energetics, and even for a qualitative discussion of folding kinetics, through the concept of the Contact Order. It also allows a simple representation of misfolded conformations and their free energy. These concepts will motivate evolutionary questions, which we will address by simulating a structurally constrained model of protein evolution, again modelled on the snake puzzle. In this way, we can discuss the analogy between evolutionary concepts and statistical mechanics that facilitates the understanding of both concepts. The proposed examples and literature are accessible, and we provide supplementary material (see ‘Data Availability’) to reproduce the numerical experiments. We also suggest possible directions to expand the unit. We hope that this work will further stimulate the adoption of games in teaching practice.

scholarly journals A thermodynamic model of protein structure evolution explains empirical amino acid rate matrices

2020 ◽  
Author(s):  
Christoffer Norn ◽  
Ingemar André ◽  
Douglas L. Theobald
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Evolutionary Dynamics ◽  
Fitness Function ◽  
Protein Structures ◽  
Evolutionary Model ◽  
Structure Evolution ◽  
Ancestral Sequences ◽  
Substitution Matrices ◽  
Nucleotide Mutation

AbstractProteins evolve under a myriad of biophysical selection pressures that collectively control the patterns of amino acid substitutions. Averaged over time and across proteins, these evolutionary pressures are sufficiently consistent to produce global substitution patterns that can be used to successfully find homologues, infer phylogenies, and reconstruct ancestral sequences. Although the factors which govern the variation of protein substitution rates has received much attention, the influence of thermodynamic stability constraints remains unresolved. Here we develop a simple model to calculate amino acid rate matrices from evolutionary dynamics controlled by a fitness function that reports on the thermodynamic effects of amino acid mutations in protein structures. This hybrid biophysical and evolutionary model accounts for nucleotide transition/transversion rate bias, multi-nucleotide codon changes, the number of codons per amino acid, and thermodynamic protein stability. We find that our theoretical model accurately recapitulates the complex pattern of empirical rates observed in common global amino acid substitution matrices used in phylogenetics. These results suggest that selection for thermodynamically stable proteins, coupled with nucleotide mutation bias filtered by the structure of the genetic code, is the primary global driver behind the amino acid substitution patterns observed in proteins throughout the tree of life.

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