Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames.
Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames.
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DOI：
10.1016/j.molcel.2023.01.023
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发表时间：
2023-03-16
期刊：
影响因子：
16
通讯作者：
Hubner, Norbert
中科院分区：
文献类型：
--
作者：
Sandmann, Clara-L.;Schulz, Jana F.;Ruiz-Orera, Jorge;Kirchner, Marieluise;Ziehm, Matthias;Adami, Eleonora;Marczenke, Maike;Christ, Annabel;Liebe, Nina;Greiner, Johannes;Schoenenberger, Aaron;Muecke, Michael B.;Liang, Ning;Moritz, Robert L.;Sun, Zhi;Deutsch, Eric W.;Gotthardt, Michael;Mudge, Jonathan M.;Prensner, John R.;Willnow, Thomas E.;Mertins, Philipp;van Heesch, Sebastiaan;Hubner, Norbert
所有物种都不断进化出短的开放阅读框架（sORF），这些框架可以作为蛋白质合成的模板，并可能为进化适应提供原料。我们分析了7,264个最近编目的人类sORF的进化起源，发现大多数在进化上都很年轻，并且是从头开始出现的。我们还发现了221个以前遗漏的sORF，它们可能被翻译成多达15个氨基酸的肽，所有这些肽都比迄今为止注释的最小的人类微蛋白小。为了研究sORF编码的小肽和年轻的微蛋白的生物活性，我们对266个候选者进行了基于质谱的相互作用组筛选和基序解析。基于这些相互作用组和额外的细胞分析，我们可以将几个候选者与mRNA剪接、翻译调节和内吞作用相关联。我们的工作为年轻和小蛋白质的进化起源和相互作用潜力提供了见解，从而有助于阐明人类蛋白质组的这一未被探索的领域。大多数sORF编码的人类微蛋白出现在灵长类动物中，并且经常从头进化。我们鉴定了小于16个氨基酸的新的人类sORF编码肽。我们在基于MS的筛选中检测了266种sORF编码蛋白的相互作用蛋白。探索人类蛋白质组中最小和进化上最年轻的成员的进化和相互作用。他们鉴定了以前未知的人类短ORF编码的微蛋白，并表明在灵长类动物中重新出现的保守和年轻的微蛋白可以参与重要的生物过程。
All species continuously evolve short open reading frames (sORFs) that can be templated for protein synthesis and may provide raw materials for evolutionary adaptation. We analyzed the evolutionary origins of 7,264 recently cataloged human sORFs and found that most were evolutionarily young and had emerged de novo. We additionally identified 221 previously missed sORFs potentially translated into peptides of up to 15 amino acids—all of which are smaller than the smallest human microprotein annotated to date. To investigate the bioactivity of sORF-encoded small peptides and young microproteins, we subjected 266 candidates to a mass-spectrometry-based interactome screen with motif resolution. Based on these interactomes and additional cellular assays, we can associate several candidates with mRNA splicing, translational regulation, and endocytosis. Our work provides insights into the evolutionary origins and interaction potential of young and small proteins, thereby helping to elucidate this underexplored territory of the human proteome. Most sORF-encoded human microproteins emerged in primates and often evolved de novo We identify new human sORF-encoded peptides that are smaller than 16 amino acids We detect interacting proteins for 266 sORF-encoded proteins in MS-based screens This study builds a resource to investigate small and evolutionarily young proteins Sandmann et al. explore the evolution and interactomes of the smallest and evolutionarily youngest members of the human proteome. They identify previously unknown human short ORF-encoded microproteins and show that conserved and young microproteins that emerged de novo in primates can engage with vital biological processes.
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