Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network
Andrew B. Kleist, Martyna Szpakowska, Lindsay J. Talbot, Greg Slodkowicz, Duccio Malinverni, Monica A. Thomas, Kyler Crawford, Daniel J. McGrail, Acacia F. Dishman, Michael J. Wedemeyer, Madison N. Sluter, S. Stephen Yi, Nidhi Sahni, Francis C. Peterson, Andy Chevigné, Brian F. Volkman, M. Madan Babu
Abstract
In humans, selective and promiscuous interactions between 46 secreted chemokine ligands and 23 cell surface chemokine receptors of the G-protein-coupled receptor (GPCR) family form a complex network to coordinate cell migration. While chemokines and their GPCRs each share common structural scaffolds, the molecular principles driving selectivity and promiscuity remain elusive. Here, we identify conserved, semi-conserved, and variable determinants (i.e., recognition elements) that are encoded and decoded by chemokines and their receptors to mediate interactions. Selectivity and promiscuity emerge from an ensemble of generalized ("public/conserved") and specific ("private/variable") determinants distributed among structured and unstructured protein regions, with ligands and receptors recognizing these determinants combinatorially. We employ these principles to engineer a viral chemokine with altered GPCR coupling preferences and provide a web resource to facilitate sequence-structure-function studies and protein design efforts for developing immuno-therapeutics and cell therapies.