Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network
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.
Authors
- Francis C. Peterson (ORCID: https://orcid.org/0000-0001-9890-4224)
- Lindsay J. Talbot (ORCID: https://orcid.org/0000-0001-7409-9873)
- Madison N. Sluter
- Andrew B. Kleist (ORCID: https://orcid.org/0000-0002-4954-010X)
- Duccio Malinverni (ORCID: https://orcid.org/0000-0002-3946-9709)
- Kyler Crawford (ORCID: https://orcid.org/0000-0002-9281-791X)
- Martyna Szpakowska (ORCID: https://orcid.org/0000-0002-5659-8377)
- Acacia F. Dishman (ORCID: https://orcid.org/0000-0002-8952-8551)
- Daniel J. McGrail (ORCID: https://orcid.org/0000-0002-6669-6069)
- Nidhi Sahni (ORCID: https://orcid.org/0000-0002-9155-5882)
- S. Stephen Yi (ORCID: https://orcid.org/0000-0003-0047-8103)
- Monica A. Thomas (ORCID: https://orcid.org/0000-0003-2513-3371)
- Michael J. Wedemeyer (ORCID: https://orcid.org/0000-0003-2213-0896)
- Greg Slodkowicz
- Brian F. Volkman (ORCID: https://orcid.org/0000-0002-6681-5179)
- M. Madan Babu (ORCID: https://orcid.org/0000-0003-0556-6196)
- Andy Chevigné (ORCID: https://orcid.org/0000-0002-8089-6665)
Institutions
- St. Jude Children's Research Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- MRC Laboratory of Molecular Biology (GB)
- Medical College of Wisconsin (US)
- Luxembourg Institute of Health (LU)
Publication Details
- Journal
- Cell
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1016/j.cell.2025.03.046
- Citations
- 4
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.18