Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues
Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues
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DOI：
10.15252/msb.20188513
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发表时间：
2019-02-01
影响因子：
9.9
通讯作者：
Gagneur, Julien
中科院分区：
文献类型：
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作者：
Eraslan, Basak;Wang, Dongxue;Gagneur, Julien
尽管它们在确定蛋白质丰度方面很重要，但控制蛋白质与mrna （PTR）比率的序列特征的综合目录和它们的作用的量化仍然缺乏。在这里，我们使用匹配的转录组和蛋白质组量化了29个人体组织中11575个蛋白质的PTR比率。我们通过回归估计了已知的蛋白质合成和降解序列决定因素的贡献，以及我们通过关联测试发现的45个mRNA和3个蛋白质序列基序。虽然PTR比率跨度超过2个数量级，但我们的综合模型预测PTR比率的中位数精度为3.2倍。报告基因分析为两个新的UTR基序提供了功能支持，固定化mRNA亲和竞争结合分析鉴定了一个基序特异性结合蛋白。此外，我们的整合模型导致了密码子最优性的新度量，该度量捕获了密码子频率对蛋白质合成和降解的影响。总之，本研究表明，人类组织中很大一部分PTR比率的变化可以从序列中预测，并确定了许多新的候选转录后调控元件。
Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2-fold. A reporter assay provided functional support for two novel UTR motifs, and an immobilized mRNA affinity competition-binding assay identified motif-specific bound proteins for one motif. Moreover, our integrative model led to a new metric of codon optimality that captures the effects of codon frequency on protein synthesis and degradation. Altogether, this study shows that a large fraction of PTR ratio variation in human tissues can be predicted from sequence, and it identifies many new candidate post-transcriptional regulatory elements.