小柯机器人

丹麦哥本哈根大学Kresten Lindorff-Larsen等研究人员合作揭示人类内在无序蛋白质组的构象组合。2024年1月31日，《自然》杂志在线发表了这项成果。

研究人员表示，内在无序蛋白质和区域（统称为“IDR”）普遍存在于各生命界的蛋白质组中，有助于形成生物功能，并与多种疾病有关。IDR具有多种瞬时形成的结构，并打破了传统的序列-结构-功能关系。蛋白质科学的发展使得在蛋白质组尺度上预测折叠蛋白质的三维结构成为可能。相比之下，人们对IDR的构象特性还缺乏了解，部分原因是无序蛋白的序列保守性很差，另外也因为只有少数这类蛋白在实验中得到了表征。无法预测整个蛋白质组中IDR的结构特性限制了人们对IDR功能作用以及演化如何塑造IDR的理解。

作为对以往单个IDR结构研究的补充，研究人员开发了一种高效的分子模型来生成IDR的构象组合，从而根据序列预测它们的构象特性。研究人员使用该模型模拟了人类蛋白质组中几乎所有的IDR。通过研究28058个IDR的构象组合，研究人员展示了链的压缩如何与细胞功能和定位相关联。研究人员深入探讨了序列特征与链压实的关系，并利用在模拟数据基础上训练的机器学习模型，展示了同源物之间构象特性的保持。这些研究结果再现了之前对单个蛋白质系统的研究结果，并举例说明了如何在蛋白质组尺度上将构象组合与细胞功能和定位、氨基酸序列、演化保守和疾病变异联系起来。研究人员免费提供的构象特性数据库将鼓励进一步的实验研究，并有助于提出有关IDR生物作用和演化的假设。

附：英文原文

Title: Conformational ensembles of the human intrinsically disordered proteome

Author: Tesei, Giulio, Trolle, Anna Ida, Jonsson, Nicolas, Betz, Johannes, Knudsen, Frederik E., Pesce, Francesco, Johansson, Kristoffer E., Lindorff-Larsen, Kresten

Issue&Volume: 2024-01-31

Abstract: Intrinsically disordered proteins and regions (collectively, IDRs) are pervasive across proteomes in all kingdoms of life, help to shape biological functions and are involved in numerous diseases. IDRs populate a diverse set of transiently formed structures and defy conventional sequence–structure–function relationships1. Developments in protein science have made it possible to predict the three-dimensional structures of folded proteins at the proteome scale2. By contrast, there is a lack of knowledge about the conformational properties of IDRs, partly because the sequences of disordered proteins are poorly conserved and also because only a few of these proteins have been characterized experimentally. The inability to predict structural properties of IDRs across the proteome has limited our understanding of the functional roles of IDRs and how evolution shapes them. As a supplement to previous structural studies of individual IDRs3, we developed an efficient molecular model to generate conformational ensembles of IDRs and thereby to predict their conformational properties from sequences4,5. Here we use this model to simulate nearly all of the IDRs in the human proteome. Examining conformational ensembles of 28,058 IDRs, we show how chain compaction is correlated with cellular function and localization. We provide insights into how sequence features relate to chain compaction and, using a machine-learning model trained on our simulation data, show the conservation of conformational properties across orthologues. Our results recapitulate observations from previous studies of individual protein systems and exemplify how to link—at the proteome scale—conformational ensembles with cellular function and localization, amino acid sequence, evolutionary conservation and disease variants. Our freely available database of conformational properties will encourage further experimental investigation and enable the generation of hypotheses about the biological roles and evolution of IDRs.

DOI: 10.1038/s41586-023-07004-5

Source: https://www.nature.com/articles/s41586-023-07004-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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