美国加州大学Nicholas T. Ingolia研究团队破译了高通量控制mRNA衰变的无序区域。该项研究成果发表在2025年4月23日出版的《自然》上。

在这里，研究组揭示了这种活动主题高通量功能分析的分子决定因素。数百个调控紊乱元件的系统诱变，结合机器学习，揭示了对其活性重要的复杂分子特征模式。芳香残基的存在和排列强有力地预测了看似不同的蛋白质序列影响mRNA稳定性和翻译的能力。课题组研究人员进一步展示了这些调控元件中有多少通过参与核心mRNA衰变机制来发挥作用。他们的研究结果定义了分子特征和生化途径，解释了无序区域如何控制mRNA表达，并揭示了功能性非结构化蛋白质的更广泛原理。

据了解，蛋白质内部的内在无序区域驱动特定的分子功能，尽管缺乏确定的结构。虽然紊乱区域是控制mRNA稳定性和翻译的组成部分，但这些调节作用的机制尚不清楚。

附：英文原文

Title: Deciphering disordered regions controlling mRNA decay in high-throughput

Author: Lobel, Joseph H., Ingolia, Nicholas T.

Issue&Volume: 2025-04-23

Abstract: Intrinsically disordered regions within proteins drive specific molecular functions despite lacking a defined structure1,2. Although disordered regions are integral to controlling mRNA stability and translation, the mechanisms underlying these regulatory effects remain unclear3. Here we reveal the molecular determinants of this activity using high-throughput functional profiling. Systematic mutagenesis across hundreds of regulatory disordered elements, combined with machine learning, reveals a complex pattern of molecular features important for their activity. The presence and arrangement of aromatic residues strongly predicts the ability of seemingly diverse protein sequences to influence mRNA stability and translation. We further show how many of these regulatory elements exert their effects by engaging core mRNA decay machinery. Our results define molecular features and biochemical pathways that explain how disordered regions control mRNA expression and shed light on broader principles within functional, unstructured proteins.

DOI: 10.1038/s41586-025-08919-x

Source: https://www.nature.com/articles/s41586-025-08919-x