Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network.

Journal: Cell
Published Date: Apr 23, 2025

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.

Authors

  • Andrew B Kleist
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI, USA; MRC Laboratory of Molecular Biology, Cambridge, UK. Electronic address: andrew.b.kleist@gmail.com.
  • Martyna Szpakowska
    Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
  • Lindsay J Talbot
    Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Greg Slodkowicz
    MRC Laboratory of Molecular Biology, Cambridge, UK.
  • Duccio Malinverni
    MRC Laboratory of Molecular Biology, Cambridge, UK; Center of Excellence for Data-Driven Discovery, Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Monica A Thomas
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Kyler S Crawford
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Daniel J McGrail
    Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Acacia F Dishman
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Michael J Wedemeyer
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Madison Sluter
    Center of Excellence for Data-Driven Discovery, Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • S Stephen Yi
    Livestrong Cancer Institutes, and Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
  • Nidhi Sahni
    Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • Francis C Peterson
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Protein Foundry, LLC, West Allis, WI, USA; Program in Chemical Biology, Medical College of Wisconsin, Milwaukee, WI, USA; Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Andy Chevigné
    Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
  • Brian F Volkman
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Protein Foundry, LLC, West Allis, WI, USA; Program in Chemical Biology, Medical College of Wisconsin, Milwaukee, WI, USA; Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: bvolkman@mcw.edu.
  • M Madan Babu
    MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.

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