Evolutionary conservation of protein functions accomplished by 3’UTR-mediated protein-protein interactions

通过 3âUTR 介导的蛋白质-蛋白质相互作用实现蛋白质功能的进化保守

• 批准号: 362707874
• 负责人: Dr. Sibylle Mitschka
• 金额: --
• 依托单位: Cancer Biology and Genetics (CBG) Program
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/362707874?language=en
• 关键词: Evolutionary; conservation; protein; functions; accomplished

Genome-wide mapping of transcript termination has revealed that about half of all human protein-coding genes produce alternative transcripts through a mechanism called alternative cleavage and polyadenylation (APA). This mechanisms leads to a substantial increase in the variety and complexity of the transcriptome. The biological role of these alternative mRNA variants, which in most cases only differ in their 3'untranslated region (3'UTR) is still not sufficiently understood. So far, research has mainly focused on the potential of these transcripts to be differentially regulated regarding mRNA stability and translational efficiency, for instance through miRNA-mediated processes. However, a recently published study by Berkovits and Mayr (Nature, 2015) could show that 3'UTRs can serve as docking sites for RNA-binding proteins which in turn mediate specific protein interactions with the nascent protein chain already at the site of translation. Specifically, it was shown that the long UTR variant of the gene CD47 is responsible for generating a pool of protein that is more efficiently transported to the plasma membrane. In contrast, protein of the short 3'UTR variant remains mostly intracellularly and fulfills anti-apoptotic functions. This new mechanism does explicitly not rely on differential mRNA localization and could potentially play an important role for a variety of proteins.Building on these findings, the aim of my fellowship proposal is to further investigate the impact of alternative 3'UTR transcript expression in the regulation of protein function. For this purpose, I want to analyze the protein interactome of four candidate genes (RAC1, GSK3B, PTEN and YAP1) with regards to differences between specific interactors of proteins generated from long and short 3'UTR transcripts of a gene. By comparing the human and chicken homologs of the investigated genes, I would like to answer the question in how far 3'UTR-mediated protein recruitment as a means to regulate protein function is conserved during evolution. Furthermore, I am also interested in elucidating the mechanisms that regulate the specificity of 3'UTR-mediated protein interactions at the molecular level. The four selected candidate genes are highly conserved in both the coding as well as the non-coding regions of the mRNA and have a high medical relevance due to their implication in different human disease. To further the understanding of the mechanisms which are responsible for the modulation of their function is therefore of particular interest. In summary, I believe that this study will offer valuable insights into the role of 3'UTRs in the regulation of protein functions.

全基因组转录终止图谱显示，大约一半的人类蛋白质编码基因通过一种称为交替切割和多聚腺苷酸化（阿帕）的机制产生交替转录本。这种机制导致转录组的多样性和复杂性大幅增加。这些替代mRNA变体的生物学作用，在大多数情况下仅在其3 '非翻译区（3'UTR）中不同，仍然没有得到充分的理解。到目前为止，研究主要集中在这些转录本在mRNA稳定性和翻译效率方面受到差异调节的潜力，例如通过miRNA介导的过程。然而，Berkovits和Mayr最近发表的一项研究（Nature，2015）可能表明，3'UTR可以作为RNA结合蛋白的对接位点，反过来介导与已经在翻译位点的新生蛋白链的特异性蛋白质相互作用。具体而言，已显示基因CD47的长UTR变体负责产生更有效地转运至质膜的蛋白质库。相比之下，短3'UTR变体的蛋白质大部分保留在细胞内并实现抗凋亡功能。这种新的机制并不依赖于差异mRNA定位，并可能发挥重要作用的各种protein.Building在这些发现的基础上，我的奖学金计划的目的是进一步研究的影响，替代3'UTR转录表达的蛋白质功能的调节。为此，我想分析四个候选基因（RAC 1，GSK3B，PTEN和YAP 1）的蛋白质相互作用组，以了解从基因的长和短3'UTR转录物产生的蛋白质的特异性相互作用物之间的差异。通过比较人类和鸡的同源基因的研究，我想回答的问题，在多大程度上3'UTR介导的蛋白质募集作为一种手段，以调节蛋白质功能是保守的进化过程中。此外，我也有兴趣在分子水平上阐明调节3'UTR介导的蛋白质相互作用的特异性的机制。所选的四个候选基因在mRNA的编码区和非编码区都高度保守，并且由于它们在不同的人类疾病中的意义而具有高度的医学相关性。因此，进一步了解负责调节其功能的机制特别有意义。总之，我相信这项研究将为3'UTR在蛋白质功能调节中的作用提供有价值的见解。