Proteome-wide analysis of PTM-dependent protein conformational changes

Intrinsically disordered regions (IDRs) of proteins are difficult to study, because they lack a defined three-dimensional structure, yet they play important biological roles. Many IDRs can mediate protein-protein interactions through regulation by post translational modifications (PTMs). IDRs also affect protein functions, as 20% of missense pathogenic mutations are present in IDRs. Understanding why disease associated mutations are located in IDRs, why protein interactions interfaces are particularly present in IDRs, and how this is linked with post-translational modifications is essential for unravelling disease mechanisms. Here we investigate how post-translational modifications globally modulate protein conformations using structural proteomics. We find that hundreds of putative structural changes are triggered by PTMs across the human proteome, recapitulating known regulatory events. The co-localization of these protein regions with known disease-associated mutations suggest that specific protein conformational changes and proteoforms pairs might be involved in the pathogenesis of genetic diseases.