title: Nonoptimal codon usage influences protein structure in intrinsically disordered regions.
abstract: Synonymous codons are not used with equal frequencies in most genomes. Codon usage has been proposed to play a role in regulating translation kinetics and co-translational protein folding. The relationship between codon usage and protein structures and the in vivo role of codon usage in eukaryotic protein folding is not clear. Here, we show that there is a strong codon usage bias in the filamentous fungus Neurospora. Importantly, we found genome-wide correlations between codon choices and predicted protein secondary structures: Nonoptimal codons are preferentially used in intrinsically disordered regions, and more optimal codons are used in structured domains. The functional importance of such correlations in vivo was confirmed by structure-based codon manipulation of codons in the Neurospora circadian clock gene frequency (frq). The codon optimization of the predicted disordered, but not well-structured regions of FRQ impairs clock function and altered FRQ structures. Furthermore, the correlations between codon usage and protein disorder tendency are conserved in other eukaryotes. Together, these results suggest that codon choices and protein structures co-evolve to ensure proper protein folding in eukaryotic organisms.
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.|State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 200237, Shanghai, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Clinical Science, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Clinical Science, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D003062:Codon; D019295:Computational Biology; D056890:Eukaryota / Q000235:genetics; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics; D005787:Gene Frequency; D016681:Genome, Fungal; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics; D009491:Neurospora / Q000235:genetics*; D017510:Protein Folding; D017433:Protein Structure, Secondary / Q000235:genetics*
chemical_list: D003062:Codon; C087405:FRQ protein, Neurospora crassa; D005656:Fungal Proteins; D064267:Intrinsically Disordered Proteins