In:
PLOS Computational Biology, Public Library of Science (PLoS), Vol. 17, No. 10 ( 2021-10-5), p. e1009461-
Abstract:
Recombinant protein production is a key process in generating proteins of interest in the pharmaceutical industry and biomedical research. However, about 50% of recombinant proteins fail to be expressed in a variety of host cells. Here we show that the accessibility of translation initiation sites modelled using the mRNA base-unpairing across the Boltzmann’s ensemble significantly outperforms alternative features. This approach accurately predicts the successes or failures of expression experiments, which utilised Escherichia coli cells to express 11,430 recombinant proteins from over 189 diverse species. On this basis, we develop TIsigner that uses simulated annealing to modify up to the first nine codons of mRNAs with synonymous substitutions. We show that accessibility captures the key propensity beyond the target region (initiation sites in this case), as a modest number of synonymous changes is sufficient to tune the recombinant protein expression levels. We build a stochastic simulation model and show that higher accessibility leads to higher protein production and slower cell growth, supporting the idea of protein cost, where cell growth is constrained by protein circuits during overexpression.
Type of Medium:
Online Resource
ISSN:
1553-7358
DOI:
10.1371/journal.pcbi.1009461
DOI:
10.1371/journal.pcbi.1009461.g001
DOI:
10.1371/journal.pcbi.1009461.g002
DOI:
10.1371/journal.pcbi.1009461.g003
DOI:
10.1371/journal.pcbi.1009461.g004
DOI:
10.1371/journal.pcbi.1009461.g005
DOI:
10.1371/journal.pcbi.1009461.s001
DOI:
10.1371/journal.pcbi.1009461.s002
DOI:
10.1371/journal.pcbi.1009461.s003
DOI:
10.1371/journal.pcbi.1009461.s004
DOI:
10.1371/journal.pcbi.1009461.s005
DOI:
10.1371/journal.pcbi.1009461.s006
DOI:
10.1371/journal.pcbi.1009461.s007
DOI:
10.1371/journal.pcbi.1009461.s008
DOI:
10.1371/journal.pcbi.1009461.s009
DOI:
10.1371/journal.pcbi.1009461.s010
DOI:
10.1371/journal.pcbi.1009461.s011
DOI:
10.1371/journal.pcbi.1009461.s012
DOI:
10.1371/journal.pcbi.1009461.s013
DOI:
10.1371/journal.pcbi.1009461.s014
DOI:
10.1371/journal.pcbi.1009461.s015
DOI:
10.1371/journal.pcbi.1009461.r001
DOI:
10.1371/journal.pcbi.1009461.r002
DOI:
10.1371/journal.pcbi.1009461.r003
DOI:
10.1371/journal.pcbi.1009461.r004
DOI:
10.1371/journal.pcbi.1009461.r005
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2193340-6
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