An inter-species protein-protein interaction network across vast evolutionary distance

In cellular systems, biophysical interactions between macromolecules underlie a complex web of functional interactions. How biophysical and functional networks are coordinated, whether all biophysical interactions correspond to functional interactions, and how such biophysical-versus-functional network coordination is shaped by evolutionary forces are all largely unanswered questions. Here, we investigate these questions using an "inter-interactome" approach. We systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network. After a billion years of evolutionary divergence, the yeast and human proteomes are still capable of forming a biophysical network with properties that resemble those of intra-species networks. Although substantially reduced relative to intra-species networks, the levels of functional overlap in the yeast-human inter-interactome network uncover significant remnants of co-functionality widely preserved in the two proteomes beyond human-yeast homologs. Our data support evolutionary selection against biophysical interactions between proteins with little or no co-functionality. Such non-functional interactions, however, represent a reservoir from which nascent functional interactions may arise. Synopsis An inter-species "inter-interactome" was generated by systematic mapping protein-protein interactions between human and yeast proteomes. Comparisons of the inter-species interactome with the two "parent" intra-species human and yeast networks reveal evolutionary constraints and plasticity of biological systems. The human and yeast proteomes widely retain the ability to form inter-species protein-protein interactions. Inter-species interactions significantly but not exclusively correspond to ancestral binding properties preserved in human and yeast proteins. Ancestral binding properties appear to underlie conserved and species-specific functions. An inter-species "inter-interactome" was generated by systematic mapping protein-protein interactions between human and yeast proteomes. Comparisons of the inter-species interactome with the two "parent" intra-species human and yeast networks reveal evolutionary constraints and plasticity of biological systems.