Structural insights into predicted protein-protein interactions and protein complexes in the human proteome.

Large-scale computational predictions of human protein-protein interactions (PPIs) have recently enabled systematic mapping of the human interactome at near-atomic resolution. In our previous work, we reported nearly 18,000 high-confidence predicted PPIs, along with selected examples that demonstrated the ability of these predictions to reveal both pairwise associations across diverse pathways and multi-subunit complex organization. Here, we extend that study by presenting additional examples of biological and biomedical interest. We highlight novel PPIs across DNA repair, mitochondrial function, and biogenesis of cilia and other organelles, where predicted interfaces provide mechanistic hypotheses for protein function and pathway crosstalk. We also illustrate how binary predictions can be assembled into models of higher-order assemblies, uncovering new candidate subunits and organizational principles for multi-protein complexes. Importantly, we integrate structural mapping of disease-associated mutations, many of which lie directly within predicted interaction interfaces, thereby offering explanations for how genetic variation may disrupt protein networks and contribute to pathology. Together, these case studies underscore how large-scale computational predictions can be distilled into detailed mechanistic insights, generating hypotheses for functional studies and expanding the structural and functional annotation of the human interactome.