Binary Interactome Models of Inner- Versus Outer-Complexome Organization

The interactome is often conceived of primarily as a collection of hundreds of multimeric machines, collectively referred to as the “complexome”. However, a large proportion of the interactome exists outside of the complexome, or in the “outer-complexome”, and may account for most of the functional plasticity exhibited by cellular systems. To compare features of inner- versus outer-complexome organization, we systematically generated a yeast all-by-all binary interactome map, integrated it with previous binary maps, and compared the resulting interactome “atlas” with systematic co-complex association and functional similarity network datasets. Direct protein-protein interactions in the inner-complexome tend to be readily detected in multiple assays and exhibit high levels of coherence with functional similarity relationships. In contrast, pairs of proteins connected by relatively transient, harder-to-detect binary interactions in the outer-complexome, exhibit higher levels of functional heterogeneity. Thus, a small proportion of the interactome corresponds to a stable, functionally homogeneous, inner-complexome, forming quaternary structure, while a much greater proportion consists of transient interactions between pairs of functionally heterogeneous proteins in the outer-complexome, forming quinary structure. ### Competing Interest Statement J.C.M. is a founder and CEO of seqWell, Inc; F.P.R. and M.V. are shareholders and scientific advisors of seqWell, Inc.