Disordered but Different: The Unique Characteristics of Intrinsically Disordered Regions in Human Transcription Factors

Intrinsically disordered regions (IDRs) of a protein have fundamentally important biological functions, including enabling multivalent interactions and driving biomolecular condensate formation. Although IDRs are widespread in the human proteome, they are significantly enriched in transcription factor (TF) activation domains. However, the evolutionary dynamics of protein disorder and whether TF IDRs systematically differ from those in other proteins remain poorly understood. Here, we comprehensively identify and analyze IDRs across the proteome and show that TF and non-TF IDRs exhibit widespread functional, phenotypic, and evolutionary differences. Strikingly, in contrast to the broader proteome, TFs have evolved to become more disordered over time. Additionally, highly disordered TFs are more likely to regulate developmental processes, govern larger regulatory networks, and be subject to stronger regulatory constraints. Finally, TF IDRs are enriched for pathogenic mutations compared to non-TF IDRs, and disorder content significantly predicts the mode of disease inheritance. Our results provide novel insights into how the evolution of gene regulation has uniquely shaped the molecular function and disease burden of TF IDRs.