Scientists map how disease mutations rewire protein interactions across the human body
Researchers identified 366 ways that disease-linked genetic mutations alter how proteins interact with each other—a finding that could accelerate drug discovery and explain why the same mutation causes different diseases in different people. The work catalogues mutations tied to cancer, metabolic disorders, and neurological conditions, offering a new roadmap for precision medicine developers and biotech companies.
Originaltitel: Proteome-scale characterisation of motif-based interactome rewiring by disease mutations
<p>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 similar to 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.</p>