全基因组和外显子组测序报告了数十万个错义突变。采用泛疾病方法，我们探索了本质无序区域（IDR）中的突变如何破坏或产生由短线性基序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，其中包含来自人类蛋白质组 IDR 的约 57,000 种肽，这些肽重叠了与癌症、代谢疾病和神经系统疾病等多种表型相关的 12,301 个单核苷酸变体。通过筛选 80 种人类蛋白质，我们发现了 366 种突变调节的相互作用，其中一半突变减少了结合，一半突变增强了结合或创建了新的相互作用界面。通过亲和力测量证实了突变的影响。在细胞测定中，验证了基序破坏性突变的影响，包括与迈尔-戈林综合征相关的突变导致细胞分裂控制蛋白 CDC45 中核定位信号的丢失。该研究提供了有关疾病相关突变如何扰乱和重新连接基于基序的相互作用组的见解。© 2024。作者。

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.© 2024. The Author(s).