Understanding the influence of codon translation rates on cotranslational protein folding

Edward P. O'Brien, Prajwal Ciryam, Michele Vendruscolo, Christopher M. Dobson

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

ConspectusProtein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics.In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome.

Original languageEnglish (US)
Pages (from-to)1536-1544
Number of pages9
JournalAccounts of Chemical Research
Volume47
Issue number5
DOIs
StatePublished - May 20 2014

Fingerprint

Protein folding
Proteins
Molecular Chaperones
ATP-Binding Cassette Transporters
Chemotherapy
Proteome
Reaction kinetics
Substitution reactions
Thermodynamics
Amino Acids
Messenger RNA
Molecules
Kinetics
Substrates

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

O'Brien, Edward P. ; Ciryam, Prajwal ; Vendruscolo, Michele ; Dobson, Christopher M. / Understanding the influence of codon translation rates on cotranslational protein folding. In: Accounts of Chemical Research. 2014 ; Vol. 47, No. 5. pp. 1536-1544.
@article{07eaa5018c404b31b0becbf50175c8e9,
title = "Understanding the influence of codon translation rates on cotranslational protein folding",
abstract = "ConspectusProtein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics.In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome.",
author = "O'Brien, {Edward P.} and Prajwal Ciryam and Michele Vendruscolo and Dobson, {Christopher M.}",
year = "2014",
month = "5",
day = "20",
doi = "10.1021/ar5000117",
language = "English (US)",
volume = "47",
pages = "1536--1544",
journal = "Accounts of Chemical Research",
issn = "0001-4842",
publisher = "American Chemical Society",
number = "5",

}

Understanding the influence of codon translation rates on cotranslational protein folding. / O'Brien, Edward P.; Ciryam, Prajwal; Vendruscolo, Michele; Dobson, Christopher M.

In: Accounts of Chemical Research, Vol. 47, No. 5, 20.05.2014, p. 1536-1544.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Understanding the influence of codon translation rates on cotranslational protein folding

AU - O'Brien, Edward P.

AU - Ciryam, Prajwal

AU - Vendruscolo, Michele

AU - Dobson, Christopher M.

PY - 2014/5/20

Y1 - 2014/5/20

N2 - ConspectusProtein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics.In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome.

AB - ConspectusProtein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics.In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome.

UR - http://www.scopus.com/inward/record.url?scp=84901289547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901289547&partnerID=8YFLogxK

U2 - 10.1021/ar5000117

DO - 10.1021/ar5000117

M3 - Article

C2 - 24784899

AN - SCOPUS:84901289547

VL - 47

SP - 1536

EP - 1544

JO - Accounts of Chemical Research

JF - Accounts of Chemical Research

SN - 0001-4842

IS - 5

ER -