Where protein structure and cell diversity meet

Protein-protein interaction networks - interactomes - are charted with the hope to understand how phenotypes emerge and how they are altered in disease states. Early efforts to map interactomes have focused on the assembly of context agnostic, reference networks. However, recent studies have mapped interactomes across different cell lines and tissues, finding highly variable interactomes due to the rewiring of protein-protein interactions in different contexts. Increasing evidence points to significant links between protein structure and interactome diversity seen across cell types and tissues. We discuss how recent findings support the key role of alternative splicing and phosphorylation, two well-established regulators of protein structural and functional diversity, in defining cell type- and tissue-specific interactomes. Moreover, we show that intrinsically disordered protein regions are most favorably equipped to support interactome rewiring by acting as hubs of protein structure and function regulation.