Buhr Florian, Jha Sujata, Thommen Michael, Mittelstaet Joerg, Kutz Felicitas, Schwalbe Harald, Rodnina Marina V, Komar Anton A
Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-Universität Frankfurt am Main, 60438 Frankfurt am Main, Germany.
Center for Gene Regulation in Health and Disease and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio 44115, USA.
Mol Cell. 2016 Feb 4;61(3):341-351. doi: 10.1016/j.molcel.2016.01.008.
In all genomes, most amino acids are encoded by more than one codon. Synonymous codons can modulate protein production and folding, but the mechanism connecting codon usage to protein homeostasis is not known. Here we show that synonymous codon variants in the gene encoding gamma-B crystallin, a mammalian eye-lens protein, modulate the rates of translation and cotranslational folding of protein domains monitored in real time by Förster resonance energy transfer and fluorescence-intensity changes. Gamma-B crystallins produced from mRNAs with changed codon bias have the same amino acid sequence but attain different conformations, as indicated by altered in vivo stability and in vitro protease resistance. 2D NMR spectroscopic data suggest that structural differences are associated with different cysteine oxidation states of the purified proteins, providing a link between translation, folding, and the structures of isolated proteins. Thus, synonymous codons provide a secondary code for protein folding in the cell.
在所有基因组中，大多数氨基酸由不止一个密码子编码。同义密码子可以调节蛋白质的产生和折叠，但密码子使用与蛋白质稳态之间的联系机制尚不清楚。在此，我们表明，编码γ-B晶状体蛋白（一种哺乳动物眼晶状体蛋白）的基因中的同义密码子变体，可调节通过Förster共振能量转移和荧光强度变化实时监测的蛋白质结构域的翻译速率和共翻译折叠速率。由密码子偏好性改变的mRNA产生的γ-B晶状体蛋白具有相同的氨基酸序列，但具有不同的构象，体内稳定性和体外蛋白酶抗性的改变表明了这一点。二维核磁共振光谱数据表明，结构差异与纯化蛋白质的不同半胱氨酸氧化状态有关，这为翻译、折叠和分离蛋白质的结构之间提供了联系。因此，同义密码子为细胞内蛋白质折叠提供了第二套编码。
