ArticleMolecular systems biology2024
Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.
Article in Molecular systems biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Variant characterization in the intrinsically disordered human proteome.Nature structural & molecular biology · 2026Article
- An Atlas of Short Linear Motif-Mediated Human Protein-Protein Interactions.bioRxiv : the preprint server for biology · 2026Article
- Systematic discovery of motif-based interactions of the auxiliary domains of USP family deubiquitinases.Nature communications · 2026Article
- Pathogenic variations illuminate functional constraints in intrinsically disordered proteins.iScience · 2026Article
- Stability and interaction defects in the Sin3A-PAH1 αα-hub domain associated with loss-of-function variants.The Journal of biological chemistry · 2026Article
- Proteoform medicine: characterizing and targeting protein forms in human disease.Nature reviews. Genetics · 2026Review
- A proteome-wide dependency map of protein interaction motifs.Nature structural & molecular biology · 2026Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Defining short linear motif binding determinants by phage display-based deep mutational scanning.Protein science : a publication of the Protein Society · 2025Article
- Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment.Nature communications · 2025Article
- Molecular determinants of condensate composition.Molecular cell · 2025Review
- The fitness cost of spurious phosphorylation.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
9 authors.
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Abstract
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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