Thanaraj T A, Argos P
European Molecular Biology Laboratory, Heidelberg, Germany.
Protein Sci. 1996 Aug;5(8):1594-612. doi: 10.1002/pro.5560050814.
Because regions on the messenger ribonucleic acid differ in the rate at which they are translated by the ribosome and because proteins can fold cotranslationally on the ribosome, a question arises as to whether the kinetics of translation influence the folding events in the growing nascent polypeptide chain. Translationally slow regions were identified on mRNAs for a set of 37 multidomain proteins from Escherichia coli with known three-dimensional structures. The frequencies of individual codons in mRNAs of highly expressed genes from E. coli were taken as a measure of codon translation speed. Analysis of codon usage in slow regions showed a consistency with the experimentally determined translation rates of codons; abundant codons that are translated with faster speeds compared with their synonymous codons were found to be avoided; rare codons that are translated at an unexpectedly higher rate were also found to be avoided in slow regions. The statistical significance of the occurrence of such slow regions on mRNA spans corresponding to the oligopeptide domain termini and linking regions on the encoded proteins was assessed. The amino acid type and the solvent accessibility of the residues coded by such slow regions were also examined. The results indicated that protein domain boundaries that mark higher-order structural organization are largely coded by translationally slow regions on the RNA and are composed of such amino acids that are stickier to the ribosome channel through which the synthesized polypeptide chain emerges into the cytoplasm. The translationally slow nucleotide regions on mRNA possess the potential to form hairpin secondary structures and such structures could further slow the movement of ribosome. The results point to an intriguing correlation between protein synthesis machinery and in vivo protein folding. Examination of available mutagenic data indicated that the effects of some of the reported mutations were consistent with our hypothesis.
由于信使核糖核酸上的区域在核糖体翻译它们的速率上存在差异，并且由于蛋白质可以在核糖体上进行共翻译折叠，因此就出现了一个问题，即翻译动力学是否会影响正在生长的新生多肽链中的折叠事件。对于一组来自大肠杆菌的37种具有已知三维结构的多结构域蛋白质，在其信使核糖核酸上鉴定出了翻译缓慢的区域。大肠杆菌中高表达基因的信使核糖核酸中各个密码子的使用频率被用作密码子翻译速度的衡量标准。对缓慢区域中密码子使用情况的分析表明，其与通过实验确定的密码子翻译速率一致；发现与同义密码子相比翻译速度更快的丰富密码子被避免使用；在缓慢区域中也发现避免使用翻译速率意外较高的稀有密码子。评估了在对应于编码蛋白质上寡肽结构域末端和连接区域的信使核糖核酸跨度上出现此类缓慢区域的统计显著性。还检查了此类缓慢区域编码的残基的氨基酸类型和溶剂可及性。结果表明，标志着高阶结构组织的蛋白质结构域边界在很大程度上由核糖核酸上的翻译缓慢区域编码，并且由对合成多肽链进入细胞质所通过的核糖体通道粘性更大的此类氨基酸组成。信使核糖核酸上翻译缓慢的核苷酸区域具有形成发夹二级结构的潜力，并且此类结构可能会进一步减缓核糖体的移动。结果表明蛋白质合成机制与体内蛋白质折叠之间存在有趣的相关性。对现有诱变数据的检查表明，一些报道的突变的影响与我们的假设一致。
