Individual cells within metazoan organisms must communicate with one another to ensure that they function collectively as a coordinated biological system. Frequently, this intercellular communication is initiated by specific extracellular protein–protein interactions involving membrane-embedded cell surface receptor proteins that transduce signals to elicit an appropriate cellular response. Because of their accessibility, cell surface proteins are considered excellent drug targets but despite their therapeutic potential, identifying extracellular interactions has remained an underexplored area due to the biochemical challenges of manipulating membrane proteins and the typically fleeting nature of their interactions.

To ultimately gain knowledge of extracellular protein:protein interactions on a genome-wide scale, we have developed a scalable assay based upon detecting direct binary binding events between hundreds of different recombinant proteins expressed in mammalian cells. The assay can be applied to a range of different biological contexts and reliably and specifically detects monomeric interactions with half-lives of less than a second and with a negligible artifactual false positive rate.

To illustrate the scalability of this approach we have systematically mapped the interactions between 630 different receptor proteins that represent the cell surface receptor repertoire of human leukocytes. We identified 28 new interactions that were independently validated, resulting in a high-confidence view of the intercellular communication that instructs human immune cells.

Finally, we have recently expanded the library to over 1500 receptor ectodomains to encompass the full receptor repertoire of tractable human receptor proteins. I will show how we are using this resource to systematically identify new targets for therapeutic antibodies, host binding proteins of autoantibodies, and host-pathogen interactions such as virus receptors.