A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions

Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for “orphan” receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets. [Display omitted] •Human IgSF interactome reveals complex network of cell-surface protein interactions•Phylogenetic homology analysis predicts protein-protein interactions•∼380 previously unknown protein-protein interactions identified•Deorphanization of receptors and new binding partners for well-studied receptors A high-throughput protein-protein interaction screen, carried out to map human cell-surface receptor-ligand interactions between proteins belonging to the immunoglobulin domain superfamily (IgSF), begins to unravel the complex network of cell-surface interactions that allows cells to recognize and respond to one another and their dynamically changing environment.