Resolving context-specific protein-protein interactomes for biological discovery and therapeutic target prioritisation

Abstract

Protein function is shaped by cellular context, yet most protein representations and interaction maps remain context-agnostic. Here we present ProtScape, a multiscale graph-learning framework integrating global protein interactions, cell-type gene expression and protein language models to learn context-specific representations and infer interactomes across more than 200 cell types. ProtScape substantially outperforms existing approaches in interaction reconstruction, increasing the area under the precision–recall curve by 40 percentage points. Its predicted interactions were supported by held-out continuous STRING global evidence, while its representations recovered higher-order protein organisation. In patient-derived amyotrophic lateral sclerosis motor neurons, ProtScape revealed stage-specific network changes implicating RAB-dependent trafficking as a candidate early disease mechanism. In Parkinson’s disease, it recovered clinically supported therapeutic targets from a proteome-wide search space 16-fold smaller than that required by competing representations. Together, ProtScape provides a scalable framework for translating context-specific interactome organisation into experimentally testable disease mechanisms and therapeutic hypotheses.