A map of human protein-protein interaction embeddings for functional discovery

Abstract

A proteins function depends not just on its own structure and localization, but also on the interactions with its partners. Many proteins are therefore better described by a set of partner-dependent roles than by a single annotation. Yet most approaches to the functional interpretation of protein-protein interactions (PPIs) remain protein or set-centric. They rely on pre-existing annotations, and perform worst where knowledge is sparse. Here, we present MAPPIE (Map of Protein-Protein Interaction Embeddings), a method that treats each PPI, rather than each protein, as a unit of representation. From 199,137 human interactions spanning 15,503 proteins, we build a two-dimensional map of the human PPI landscape for functional discovery. Protein language model embeddings for two protein interaction partners are combined and compressed into a latent space, with model selection guided by domain-domain interactions used as a structural proxy for interaction similarity. The resulting geometry separates domain defined interaction classes, organizes disorder associated interactions spatially, and splits interactions involving the same protein by partner. A query PPIs latent neighbourhood recovers its own annotated functions across molecular, complex, pathway, and biological processes. MAPPIE contributes most where existing functional evidence is weakest, outperforming interactome and sequence identity baselines for sparsely connected interactions. MAPPIE neighbours of query PPIs are enriched for partners in independent protein networks, recovering curated complex-level function even when subunits are spread across the map. Applied to a human dark interactome, MAPPIE assigns specific, experimentally supported functions to dark hub proteins.