Proteome-scale characterisation of protein motif interactome rewiring by disease mutations

Abstract

AbstractWhole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in the intrinsically disordered regions (IDRs) break or generate short linear motifs. We created a peptide-phage display library tiling peptides overlapping 12,301 disease-associated mutations from the IDRs of the human proteome. The mutations are linked to diverse diseases including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins we found 367 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing 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 a panoramic view of how disease-associated mutations perturb and rewire the motif-based interactome.