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.
journal_name
Proc Natl Acad Sci U S Aauthors
Walsh IM,Bowman MA,Soto Santarriaga IF,Rodriguez A,Clark PLdoi
10.1073/pnas.1907126117subject
Has Abstractpub_date
2020-02-18 00:00:00pages
3528-3534issue
7eissn
0027-8424issn
1091-6490pii
1907126117journal_volume
117pub_type
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