Summary Hundreds of different protein complexes that perform important functions across all cellular processes, collectively comprising the “complexome” of an organism, have been identified 1 . However, less is known about the fraction of the interactome that exists outside the complexome, in the “outer-complexome”. To investigate features of “inner”- versus outer-complexome organisation in yeast, we generated a high-quality atlas of binary protein-protein interactions (PPIs), combining three previous maps 2–4 and a new reference all-by-all binary interactome map. A greater proportion of interactions in our map are in the outer-complexome, in comparison to those found by affinity purification followed by mass spectrometry 5–7 or in literature curated datasets 8–11 . In addition, recent advances in deep learning predictions of PPI structures 12 mirror the existing experimentally resolved structures in being largely focused on the inner complexome and missing most interactions in the outer-complexome. Our new PPI network suggests that the outer-complexome contains considerably more PPIs than the inner-complexome, and integration with functional similarity networks 13–15 reveals that interactions in the inner-complexome are highly detectable and correspond to pairs of proteins with high functional similarity, while proteins connected by more transient, harder-to-detect interactions in the outer-complexome, exhibit higher functional heterogeneity.

Binary interactome models of inner- versus outer-complexome organisation