A Survey of Predicted Protein-Protein Interactions Involving Disordered Regions in Humans.

Intrinsically disordered regions (IDRs) in proteins play a pivotal role in protein-protein interactions (PPIs). Using AlphaFold2 and enriched multiple sequence alignments, we predicted and investigated PPIs across the human proteome, focusing on those involving disordered regions. Our predictions show that disordered regions predominantly interact with ordered domains, whereas predicted disordered-disordered interactions are relatively rare. Although disordered regions typically lack annotated domains, certain regions-such as the keratin type II head domain and the Krüppel-associated box (KRAB)-mediate specific interactions. In contrast, their predicted binding partners frequently feature diverse Pfam domains, including protein kinase, WD40 repeat, and nuclear hormone receptor domains. These domains are enriched in nuclear localization and α-helical repeat motifs. Disordered regions involved in predicted PPIs exhibit higher sequence conservation than non-interacting disordered regions, suggesting evolutionary constraints at interaction interfaces. Moreover, certain posttranslational modifications (e.g., phosphorylation and acetylation) in disordered regions are enriched within predicted interaction interfaces, likely modulating binding affinities. Notably, we identified a significant enrichment of disease-associated mutations in predicted PPI interfaces involving disordered regions, underscoring their functional and pathological relevance. Together, these findings highlight the intricate interplay between disordered and ordered regions in mediating PPIs and provide insights into their structural and functional contributions to human health and disease.