以蛋白质组尺度描述疾病突变导致的基于主题的相互作用组重配。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular Systems Biology Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI:10.1038/s44320-024-00055-4
Johanna Kliche, Leandro Simonetti, Izabella Krystkowiak, Hanna Kuss, Marcel Diallo, Emma Rask, Jakob Nilsson, Norman E Davey, Ylva Ivarsson
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引用次数: 0

摘要

全基因组和外显子组测序报告了数十万个错义突变。我们采用泛疾病方法,探索了内在无序区(IDRs)的突变如何打破或产生由短线性基团介导的蛋白质相互作用。我们创建了一个肽-噬菌体展示文库,从人类蛋白质组的IDRs中筛选出约57,000个肽,与12,301个与癌症、代谢性疾病和神经系统疾病等不同表型相关的单核苷酸变异重叠。通过筛选 80 种人类蛋白质,我们发现了 366 种突变调控的相互作用,其中一半的突变降低了结合力,一半的突变增强了结合力或创造了新的相互作用界面。突变的影响通过亲和力测量得到了证实。在细胞实验中,我们验证了基因突变对图案的破坏作用,包括细胞分裂控制蛋白 CDC45 因与梅尔-戈林综合征有关的突变而失去核定位信号。这项研究深入揭示了与疾病相关的突变如何扰乱和重新连接基于主题的相互作用组。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.

Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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