title: Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD.
abstract: Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. To investigate the in vivo role of codon usage in animals, we took advantage of the sensitivity and robustness of the Drosophila circadian system. By codon-optimizing parts of Drosophila period (dper), a core clock gene that encodes a critical component of the circadian oscillator, we showed that dper codon usage is important for circadian clock function. Codon optimization of dper resulted in conformational changes of the dPER protein, altered dPER phosphorylation profile and stability, and impaired dPER function in the circadian negative feedback loop, which manifests into changes in molecular rhythmicity and abnormal circadian behavioral output. This study provides an in vivo example that demonstrates the role of codon usage in determining protein structure and function in an animal system. These results suggest a universal mechanism in eukaryotes that uses a codon usage "code" within genetic codons to regulate cotranslational protein folding.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Jingjing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Entomology and Nematology, University of California at Davis, Davis, California 95616, USA;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Murphy
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Entomology and Nematology, University of California at Davis, Davis, California 95616, USA;
authors.forename: Ying H
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Entomology and Nematology, University of California at Davis, Davis, California 95616, USA;
authors.forename: Vu H
authors.initials: VH
authors.lastname: Lam
authors.affiliation: Department of Entomology and Nematology, University of California at Davis, Davis, California 95616, USA;
authors.forename: Christine A
authors.initials: CA
authors.lastname: Tabuloc
authors.affiliation: Department of Entomology and Nematology, University of California at Davis, Davis, California 95616, USA;
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Chiu
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics*; D003062:Codon / Q000235:genetics*; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D025461:Feedback, Physiological; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D003062:Codon; D029721:Drosophila Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins
keywords: Drosophila; circadian clock; codon usage; period; protein structure