Silent mutations affect in vivo protein folding in Escherichia coli

Cortazzo, Patricia; Červeñanský, Carlos; Marı́n, Mónica; Reiss, Claude; Ehrlich, Ricardo; Deana, Atilio

doi:10.1016/s0006-291x(02)00226-7

Cited by 162 publications

(116 citation statements)

References 29 publications

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“…Understanding the process by which proteins fold during their biosynthesis is one of the most fundamental problems in molecular biology, as it is crucial to enable their biological function 3,40 , and its failure can result in their misfolding [40][41][42] , malfunction 7 and aggregation 3,4,43 , events that are associated with a wide range of severe health conditions including neurodegenerative disease 44 . A key challenge in this context is to interpret and predict the influence of individual codon translation rates on cotranslational protein folding and misfolding.…”

Section: Discussionmentioning

confidence: 99%

Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates

O’Brien

Vendruscolo

2014

Nat Commun

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It has been observed for several proteins that slowing down the rate at which individual codons are translated can increase their probability of cotranslational protein folding, while speeding up codon translation can decrease it. Here we investigate whether or not this inverse relationship between translation speed and the cotranslational folding probability is a general phenomenon or if other scenarios are possible. We first derive chemical kinetic equations that relate individual codon translation rates to the probability that a domain will fold, populate an intermediate or misfold, and examine the cotranslational folding scenarios that are possible within these models. We find that speeding up codon translation through misfolding-prone segments can, in some cases, increase the folding probability of a domain immediately before the nascent protein is released from the ribosome and decrease its chances of misfolding. Thus, for some proteins fast-translating codons could be as important as slow-translating codons in coordinating cotranslational protein folding.

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Section: Discussionmentioning

confidence: 99%

Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates

O’Brien

Vendruscolo

2014

Nat Commun

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“…(i) During the expression in E. coli of EgFABP, a small fatty acid binding protein from E. granulosus, rare codons encoding a turn between two alpha helices were substituted by frequent ones. The expression of one frequent synonymous variant showed reduced solubility and triggered the activity of a heat shock promoter driving the expression of a reporter gene, indicating the presence of unfolded or misfolded proteins (Cortazzo et al 2002). Therefore, in this case, the use of frequent codons, instead of being an advantage, led to protein misfolding and in vivo aggregation.…”

Section: Translation Kineticsmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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“…However, these rates may vary with p. For example, increasing protein translation rates has been shown to increase the probability a protein is misfolded (Komar et al, 1999;Cortazzo et al, 2002). Thus assuming that misfolded proteins are not all destroyed and consequently that some are used by the virus, misfolding can lead to increases in c and reductions in k. If a virus has adapted to reduce the antigenicity of its envelope proteins, misfolded proteins could lead to greater antibody binding to free virus, which would in turn lead to an increase in the virion's average clearance rate c. Similarly, misfolded envelope proteins would be expected to have a lower target cell binding rate, thus directly decreasing k. Finally, misfolded viral proteins involved in post cell-invasion processes, such as reverse transcription, should have lower enzymatic activities and shorter intracellular half-lives (and hence concentrations).…”

Section: Linking Production To Other Termsmentioning

confidence: 99%

Optimizing within-host viral fitness: infected cell lifespan and virion production rate

Gilchrist

Coombs

Perelson

2004

Journal of Theoretical Biology

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We explore how an infected cell's virion production rate can affect the relative fitness of a virus within a host. We perform an invasion analysis, based on an age-structured model of viral dynamics, to derive the within-host relative viral fitness. We find that for chronic infections, in the absence of trade-offs between viral life history stages, natural selection favors viral strains whose virion production rate maximizes viral burst size. We then show how various life history trade-offs such as that between virion production and immune system recognition and clearance of virally infected cells can lead to natural selection favoring production rates lower than the one that maximizes burst size. Our findings suggest that HIV replication rates should vary between cells with different life spans, as has been suggested by recent observation. Published by Elsevier Ltd.

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Silent mutations affect in vivo protein folding in Escherichia coli

Cited by 162 publications

References 29 publications

Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates

Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates

Protein folding and tRNA biology

Optimizing within-host viral fitness: infected cell lifespan and virion production rate

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