Widespread position-specific conservation of synonymous rare codons within coding sequences.
Widespread position-specific conservation of synonymous rare codons within coding sequences.
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DOI：
10.1371/journal.pcbi.1005531
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发表时间：
2017-05
影响因子：
4.3
通讯作者：
Clark PL
中科院分区：
文献类型：
--
作者：
Chaney JL;Steele A;Carmichael R;Rodriguez A;Specht AT;Ngo K;Li J;Emrich S;Clark PL
同义稀有密码子被认为是基因表达的次优密码子，因为它们比普通密码子翻译得更慢。然而令人惊讶的是，许多蛋白质编码序列包括大簇的同义稀有密码子。编码序列的5'末端的稀有密码子已显示出增加翻译效率。虽然一般的功能作用的同义罕见密码子内编码序列还没有建立，最近的几份报告已经确定了罕见的常见同义密码子取代，损害折叠的编码蛋白质。在这里，我们测试的假设，虽然同义密码子的使用频率从生物体到生物体的变化，密码子的稀有性将在一组同源编码序列的特定位置上是保守的，例如，在不改变蛋白质序列的情况下调整翻译速率。这种稀有性的保守-而不是特定的密码子身份-可以协调编码蛋白质的共翻译折叠。我们证明，许多罕见的密码子簇的位置确实是保守的同源编码序列在不同的真核生物，细菌和古细菌物种，这表明他们从积极的选择结果，并具有功能性的作用。大多数保守的罕见密码子簇发生在保守的蛋白质结构域内而不是之间，挑战了它们的主要功能是在自主结构单元合成后促进共翻译折叠的观点。相反，许多保守的稀有密码子簇在结构域内分离较小的蛋白质结构基序。这些较小的基序通常比整个结构域折叠得更快，在时间尺度上与同义密码子使用的翻译速率调节更一致。虽然具有保守的稀有密码子簇的蛋白质在结构和功能上是多样的，但它们富含与生物体生长和发育相关的功能，这表明同义密码子使用在生物体生理学中的重要作用。保守的稀有密码子簇的鉴定推进了我们对同义密码子的不同功能作用的理解，并使同义密码子使用对功能蛋白质产生的影响的实验测试成为可能。蛋白质是长的线性聚合物，必须折叠成复杂的三维形状，以执行其细胞功能。每个蛋白质都是由核糖体合成的，核糖体解码mRNA编码序列中的每个三核苷酸密码子，以选择将占据蛋白质序列中每个位置的氨基酸残基。大多数氨基酸可以由一个以上的密码子编码，但这些同义密码子的使用频率并不相同。稀有密码子通常与较慢的蛋白质合成速率相关，因此传统上被认为对有效的蛋白质生产有轻度危害。然而，由于同义密码子替换并不改变编码蛋白的序列，大多数观点认为它们仅仅反映了基因组的“背景噪声”。相反，在这里，我们表明，许多同义的稀有密码子的位置是保守的mRNA序列编码结构相似的蛋白质从不同的生物体。这些结果表明，稀有密码子具有与功能蛋白质的产生相关的功能作用，可能调节蛋白质合成的速率和蛋白质折叠的最早步骤，而合成仍在进行中。
Synonymous rare codons are considered to be sub-optimal for gene expression because they are translated more slowly than common codons. Yet surprisingly, many protein coding sequences include large clusters of synonymous rare codons. Rare codons at the 5’ terminus of coding sequences have been shown to increase translational efficiency. Although a general functional role for synonymous rare codons farther within coding sequences has not yet been established, several recent reports have identified rare-to-common synonymous codon substitutions that impair folding of the encoded protein. Here we test the hypothesis that although the usage frequencies of synonymous codons change from organism to organism, codon rarity will be conserved at specific positions in a set of homologous coding sequences, for example to tune translation rate without altering a protein sequence. Such conservation of rarity–rather than specific codon identity–could coordinate co-translational folding of the encoded protein. We demonstrate that many rare codon cluster positions are indeed conserved within homologous coding sequences across diverse eukaryotic, bacterial, and archaeal species, suggesting they result from positive selection and have a functional role. Most conserved rare codon clusters occur within rather than between conserved protein domains, challenging the view that their primary function is to facilitate co-translational folding after synthesis of an autonomous structural unit. Instead, many conserved rare codon clusters separate smaller protein structural motifs within structural domains. These smaller motifs typically fold faster than an entire domain, on a time scale more consistent with translation rate modulation by synonymous codon usage. While proteins with conserved rare codon clusters are structurally and functionally diverse, they are enriched in functions associated with organism growth and development, suggesting an important role for synonymous codon usage in organism physiology. The identification of conserved rare codon clusters advances our understanding of distinct, functional roles for otherwise synonymous codons and enables experimental testing of the impact of synonymous codon usage on the production of functional proteins. Proteins are long linear polymers that must fold into complex three-dimensional shapes in order to carry out their cellular functions. Every protein is synthesized by the ribosome, which decodes each trinucleotide codon in an mRNA coding sequence in order to select the amino acid residue that will occupy each position in the protein sequence. Most amino acids can be encoded by more than one codon, but these synonymous codons are not used with equal frequency. Rare codons are associated with generally slower rates for protein synthesis, and for this reason have traditionally been considered mildly deleterious for efficient protein production. However, because synonymous codon substitutions do not change the sequence of the encoded protein, the majority view is that they merely reflect genomic ‘background noise’. To the contrary, here we show that the positions of many synonymous rare codons are conserved in mRNA sequences that encode structurally similar proteins from a diverse range of organisms. These results suggest that rare codons have a functional role related to the production of functional proteins, potentially to regulate the rate of protein synthesis and the earliest steps of protein folding, while synthesis is still underway.