Where protein structure and cell diversity meet

Interactomes vary considerably across different cell lines and tissues. A two faceted view of tissue/cell type-specific interactomes is emerging. Interactions that are conserved across contexts occur between evolutionarily old proteins that interact to form housekeeping complexes. Interactions that are rewired across contexts occur between evolutionarily young proteins that interact preferentially with each other to carry out specialized functions. Protein structural diversity, mediated by intrinsically disordered regions, alternative splicing, and post-translational modifications, contributes significantly to the tissue/cell type-specific diversity of interactomes. By contrast, changes in protein abundance can only explain some interactome rewiring events. Context-aware interactomes are helping us understand the phenotypic effect of disease variants by placing mutated proteins in relevant biological contexts. 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. 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. process resulting in the inclusion or exclusion of exons that create multiple mRNA isoforms from a single gene. in affinity purification followed by mass spectrometry, baits are created by epitope-tagging proteins of interest with short peptides or proteins that can easily be purified. Recovery of bait proteins on a matrix recognizing the epitope retrieves proteins that the bait interacts with and allows the identification of protein–protein interactions. an evolutionarily conserved complex comprising eight proteins that controls protein ubiquitination. short peptide stretches that interact with specific protein-binding domains. the whole set of physical protein–protein interactions present within a cell. a type of PTM where a phosphate group is covalently linked by enzymes to the side chains of serine, threonine, and tyrosine in eukaryotes and also histidine in prokaryotes. chemical modification of a protein at amino acid side chains or at the N or C terminus. a binary protein–protein interaction assay where one protein is fused to a DNA-binding domain (DB) and another protein is fused to an activation domain (AD). Both proteins are expressed in yeast and their interaction brings the DB and AD together, reconstituting the activity of a transcription factor, which drives the expression of a reporter gene.