Systems-wide Identification of cis-Regulatory Elements in Proteins

Protein interactions in cis that can activate or autoinhibit protein function play an important role in the fine-tuning of regulatory and signaling processes in the cell, but thus far cis-regulatory elements (CREs) in proteins have not been systematically identified and studied. Here, we introduce a computational tool that identifies intrinsically disordered protein segments that contribute to protein function regulation via interactions in cis. We apply this tool to estimate the prevalence of CREs in the human proteome and reveal that cis regulation is enriched in several signaling pathways, including the MAP kinase pathway, for which we provide a detailed map of its "cis regulome." We also show that disease-causing mutations are highly enriched in CREs, but not in motifs that classically mediate protein-protein interactions of disordered protein segments. Our approach should facilitate the discovery and characterization of CREs in proteins and the identification of disease-causing mutations that disrupt protein regulation in cis.