Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness.

Abstract:

:In the cell, proteins are synthesized from N to C terminus and begin to fold during translation. Cotranslational folding mechanisms are therefore linked to elongation rate, which varies as a function of synonymous codon usage. However, synonymous codon substitutions can affect many distinct cellular processes, which has complicated attempts to deconvolve the extent to which synonymous codon usage can promote or frustrate proper protein folding in vivo. Although previous studies have shown that some synonymous changes can lead to different final structures, other substitutions will likely be more subtle, perturbing predominantly the protein folding pathway without radically altering the final structure. Here we show that synonymous codon substitutions encoding a single essential enzyme lead to dramatically slower cell growth. These mutations do not prevent active enzyme formation; instead, they predominantly alter the protein folding mechanism, leading to enhanced degradation in vivo. These results support a model in which synonymous codon substitutions can impair cell fitness by significantly perturbing cotranslational protein folding mechanisms, despite the chaperoning provided by the cellular protein homeostasis network.

authors

Walsh IM,Bowman MA,Soto Santarriaga IF,Rodriguez A,Clark PL

doi

10.1073/pnas.1907126117

subject

Has Abstract

pub_date

2020-02-18 00:00:00

pages

3528-3534

issue

7

eissn

0027-8424

issn

1091-6490

pii

1907126117

journal_volume

117

pub_type

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