The Center for Gene Regulation in Health and Disease (GRHD)
Cleveland State University
Host: John Hunt
Title: "Codon usage - a guide for protein folding in the cell"
Abstract: For any protein to function properly, the polypeptide chain produced by the ribosome has to fold into a correct three-dimensional structure. Protein folding in vivo begins co-translationally when the nascent peptide emerges from the ribosome exit tunnel. We and others suggested that choice of synonymous codons in mRNA may alter the properties of a protein; however, the mechanisms behind such effects remained unclear. Here we show how the use of different synonymous codons results in a change of local and global translational kinetics, altering the pathway of co-translational folding, as well as the ultimate stable conformation attained by a model protein, mammalian eye lens gamma-B crystallin, as assessed by 2D-NMR. We investigate translation and co-translational folding in a time-resolved manner, providing evidence that the structural difference between synonymous variants arise at the level of co-translational folding. Our study provides important insights into the mechanism of protein folding in the cell and contributes to better understanding of the relationship between degeneracy of the genetic code, genotype and phenotype, origin of human diseases caused by synonymous mutations leading to incorrect protein folding and gives a tool to upscale and evaluate the production of functional proteins for medical and biotechnological purposes.
Key Recent Refs:
Simhadri et al, Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B. J Med Genet., 2016.
Komar AA. The yin and yang of codon usage. Hum Mol Genet., 2016.
Buhr et al, Synonymous codons direct cotranslational folding toward different protein conformations. Mol. Cell, 2016.
Holtkamp et al, Cotranslational protein folding on the ribosome monitored in real time. Science, 2015
Komar AA. A pause for thought along the co-translational folding pathway. Trends Biochem Sci. 2009.