Cache Domains That are Homologous to, but Different from PAS Domains Comprise the Largest Superfamily of Extracellular Sensors in Prokaryotes

Cellular receptors usually contain a designated sensory domain that recognizes the signal. Per/Arnt/Sim (PAS) domains are ubiquitous sensors in thousands of species ranging from bacteria to humans. Although PAS domains were described as intracellular sensors, recent structural studies revealed PAS-like domains in extracytoplasmic regions in several transmembrane receptors. However, these structurally defined extracellular PAS-like domains do not match sequence-derived PAS domain models, and thus their distribution across the genomic landscape remains largely unknown. Here we show that structurally defined extracellular PAS-like domains belong to the Cache superfamily, which is homologous to, but distinct from the PAS superfamily. Our newly built computational models enabled identification of Cache domains in tens of thousands of signal transduction proteins including those from important pathogens and model organisms. Furthermore, we show that Cache domains comprise the dominant mode of extracellular sensing in prokaryotes.Author Summary: Cell-surface receptors control multiple cellular functions and are attractive targets for drug design. These receptors often have dedicated extracellular domains that bind signaling molecules, such as hormones and nutrients. Computational identification of these ligand-binding domains in genomic sequences is a pre-requisite for their further experimental characterization. Using available three-dimensional structures of several bacterial cell-surface receptors, we built computational models that enabled identification of the Cache domain, as the most common extracellular sensor module in prokaryotes, including many important pathogens. We also demonstrated that the Cache domain is homologous to, but sufficiently different from the most common intracellular sensor module, the PAS domain. These findings provide a unified view on molecular principles of signal recognition by extra- and intracellular receptors.