Silent substitutions predictably alter translation elongation rates and protein folding efficiencies.
Silent substitutions predictably alter translation elongation rates and protein folding efficiencies.
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DOI：
10.1016/j.jmb.2012.06.010
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发表时间：
2012-09-21
影响因子：
5.6
通讯作者：
Barral, Jose M.
中科院分区：
文献类型：
--
作者：
Spencer, Paige S.;Siller, Efrain;Anderson, John F.;Barral, Jose M.
遗传密码冗余允许大多数氨基酸由多个密码子编码，这些密码子沿着编码序列非随机分布。一种公认的理论解释了这种非均匀密码子选择的生物学意义，即密码子的翻译速度不同。因此，沿信息的不同密码子位置可能导致多肽从核糖体中出现的速率不同，这可能影响向自然状态折叠的能力。以前的研究报告了关于某些密码子是否与编码蛋白质的特定结构或折叠属性相关的相互矛盾的结果。这在一定程度上是由于传统上用于预测密码子翻译速度的不同标准，包括它们的使用频率和能够解码它们的tRNA物种的浓度，这并不总是相关的。在这里，我们开发了一种度量来基于tRNA解码机制的可用性来预测生物特定密码子的相对翻译率：Watson-Crick、非Watson-Crick或两种类型的相互作用。我们通过在活的大肠杆菌细胞中进行脉冲追逐分析来确定信息的翻译率，并表明基于这些概念的序列工程以一种优于密码子使用频率的方式可预测地调制翻译率，发生在延伸阶段，并显著影响编码多肽的折叠。最后，我们证明了基于表达宿主tRNA池的序列协调，旨在模拟原始生物体的核糖体运动，可以显著增加编码多肽的折叠。这些结果阐明了遗传密码简并可能如何发挥作用，以指定氨基酸编码以外的特性，包括折叠。
Genetic code redundancy allows most amino acids to be encoded by multiple codons which are non-randomly distributed along coding sequences. An accepted theory explaining the biological significance of such non-uniform codon selection is that codons are translated at different speeds. Thus, varying codon placement along a message may confer variable rates of polypeptide emergence from the ribosome, which may influence the capacity to fold towards the native state. Previous studies report conflicting results regarding whether certain codons correlate with particular structural or folding properties of the encoded protein. This is partly due to different criteria traditionally utilized for predicting translation speeds of codons, including their usage frequencies and the concentration of tRNA species capable of decoding them, which do not always correlate. Here, we developed a metric to predict organism-specific relative translation rates of codons based on the availability of tRNA decoding mechanisms: Watson-Crick, non-Watson-Crick or both types of interactions. We determine translation rates of messages by pulse-chase analyses in living E. coli cells and show that sequence engineering based on these concepts predictably modulates translation rates in a manner that is superior to codon usage frequency, occur during the elongation phase, and significantly impacts folding of the encoded polypeptide. Finally, we demonstrate that sequence harmonization based on expression host tRNA pools, designed to mimic ribosome movement of the original organism, can significantly increase the folding of the encoded polypeptide. These results illuminate how genetic code degeneracy may function to specify properties beyond amino acid encoding, including folding.
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影响因子：
16
作者：
Johansson, Magnus;Bouakaz, Elli;Ehrenberg, Mans
通讯作者：
Ehrenberg, Mans
影响因子：
5.6
作者：
Siller, Efrain;DeZwaan, Diane C.;Barral, Jose M.
通讯作者：
Barral, Jose M.
影响因子：
14.9
作者：
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通讯作者：
Pan T
影响因子：
6
作者：
Spencer PS;Barral JM
通讯作者：
Barral JM
影响因子：
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作者：
PEDERSEN, S
通讯作者：
PEDERSEN, S