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 S. Crawford; Daniel J. McGrail; Acacia F. Dishman; Michael J. Wedemeyer; Madison Sluter; S. Stephen Yi; Nidhi Sahni; Francis C. Peterson; Andy Chevigné; Brian F. Volkman; M. Madan Babu

doi:10.1016/j.cell.2025.03.046

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 S. Crawford
, Daniel J. McGrail
, Acacia F. Dishman
, Michael J. Wedemeyer
, Madison Sluter
, S. Stephen Yi
, Nidhi Sahni
, Francis C. Peterson
, Andy Chevigné
, Brian F. Volkman^*
, M. Madan Babu^*

^*Corresponding author for this work

Immuno-Pharmacology and Interactomics

Research output: Contribution to journal › Article › Research › peer-review

6 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3603-3622.e27
Number of pages	48
Journal	Cell
Volume	188
Issue number	13
Early online date	21 Apr 2025
DOIs	https://doi.org/10.1016/j.cell.2025.03.046
Publication status	Published - 26 Jun 2025

Keywords

chemokine
chemotaxis
data science
GPCR
machine learning
polymorphism
protein-protein interaction
selectivity determinants
short linear motif
unstructured protein
Amino Acid Sequence
Humans
Models, Molecular
Chemokines/metabolism
Receptors, Chemokine/metabolism
Receptors, G-Protein-Coupled/metabolism
Protein Binding
Ligands

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Kleist, A. B., Szpakowska, M., Talbot, L. J., Slodkowicz, G., Malinverni, D., Thomas, M. A., Crawford, K. S., McGrail, D. J., Dishman, A. F., Wedemeyer, M. J., Sluter, M., Yi, S. S., Sahni, N., Peterson, F. C., Chevigné, A., Volkman, B. F., & Babu, M. M. (2025). Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network. Cell, 188(13), 3603-3622.e27. https://doi.org/10.1016/j.cell.2025.03.046

@article{b957ca36dbf240f3b6a446ccf515e15e,

title = "Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network",

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.",

keywords = "chemokine, chemotaxis, data science, GPCR, machine learning, polymorphism, protein-protein interaction, selectivity determinants, short linear motif, unstructured protein, Amino Acid Sequence, Humans, Models, Molecular, Chemokines/metabolism, Receptors, Chemokine/metabolism, Receptors, G-Protein-Coupled/metabolism, Protein Binding, Ligands",

author = "Kleist, \{Andrew B.\} and Martyna Szpakowska and Talbot, \{Lindsay J.\} and Greg Slodkowicz and Duccio Malinverni and Thomas, \{Monica A.\} and Crawford, \{Kyler S.\} and McGrail, \{Daniel J.\} and Dishman, \{Acacia F.\} and Wedemeyer, \{Michael J.\} and Madison Sluter and Yi, \{S. Stephen\} and Nidhi Sahni and Peterson, \{Francis C.\} and Andy Chevign{\'e} and Volkman, \{Brian F.\} and Babu, \{M. Madan\}",

note = "Funding: This work was supported by American Lebanese Syrian Associated Charities (to M.M.B., D.M., M. Sluter, and L.J.T.); Medical Research Council grants MC\_U105185859 (to M.M.B., D.M., and G.S.); The Lister Institute for Preven- tative Medicine (to M.M.B. and A.B.K.); NIH grants F30CA196040 (to A.B.K.), R37AI058072 (to B.F.V.), F30HL134253 (to M.A.T.), F30CA236182 (to A.F.D.), T32GM080202 (to A.B.K., M.A.T., K.S.C., and A.F.D.), R35GM137836 (to N.S.), K99CA240689 (to D.J.M.); Luxembourg Institute of Health NanoLux Platform (to M. Szpakowska and A.C.); Luxembourg National Research Fund INTER/FNRS grants INTER 20/15084569 and CORE C23/BM/ 18068832 (to M. Szpakowska and A.C.); F.R.S.-FNRS-Te´ le´ vie grants 7.8504.20, 7.4502.21, and 7.8508.22 (M. Szpakowska and A.C.); St. Jude GPCR Research Collaborative (to M.M.B.); AstraZeneca Blue Sky Fund grant BSF17 (to M.M.B. and G.S.); Swiss National Science Foundation grant P2ELP3\_18910 (to D.M.); CPRIT Scholar in Cancer Research grant RR160021 (to N.S.); Alfred P. Sloan Scholar Research Fellowship grant FG- 2018-10723 (to N.S.); Blanton-Davis Ovarian Cancer Research Program (to N.S.); Andrew Sabin Family Foundation Fellowship (to N.S.); Ovarian Cancer Research Alliance Early Career Award grant 649968 (to N.S.). Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = jun,

day = "26",

doi = "10.1016/j.cell.2025.03.046",

language = "English",

volume = "188",

pages = "3603--3622.e27",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "13",

}

Kleist, AB, Szpakowska, M, Talbot, LJ, Slodkowicz, G, Malinverni, D, Thomas, MA, Crawford, KS, McGrail, DJ, Dishman, AF, Wedemeyer, MJ, Sluter, M, Yi, SS, Sahni, N, Peterson, FC, Chevigné, A, Volkman, BF & Babu, MM 2025, 'Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network', Cell, vol. 188, no. 13, pp. 3603-3622.e27. https://doi.org/10.1016/j.cell.2025.03.046

TY - JOUR

T1 - Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network

AU - Kleist, Andrew B.

AU - Szpakowska, Martyna

AU - Talbot, Lindsay J.

AU - Slodkowicz, Greg

AU - Malinverni, Duccio

AU - Thomas, Monica A.

AU - Crawford, Kyler S.

AU - McGrail, Daniel J.

AU - Dishman, Acacia F.

AU - Wedemeyer, Michael J.

AU - Sluter, Madison

AU - Yi, S. Stephen

AU - Sahni, Nidhi

AU - Peterson, Francis C.

AU - Chevigné, Andy

AU - Volkman, Brian F.

AU - Babu, M. Madan

N1 - Funding: This work was supported by American Lebanese Syrian Associated Charities (to M.M.B., D.M., M. Sluter, and L.J.T.); Medical Research Council grants MC_U105185859 (to M.M.B., D.M., and G.S.); The Lister Institute for Preven- tative Medicine (to M.M.B. and A.B.K.); NIH grants F30CA196040 (to A.B.K.), R37AI058072 (to B.F.V.), F30HL134253 (to M.A.T.), F30CA236182 (to A.F.D.), T32GM080202 (to A.B.K., M.A.T., K.S.C., and A.F.D.), R35GM137836 (to N.S.), K99CA240689 (to D.J.M.); Luxembourg Institute of Health NanoLux Platform (to M. Szpakowska and A.C.); Luxembourg National Research Fund INTER/FNRS grants INTER 20/15084569 and CORE C23/BM/ 18068832 (to M. Szpakowska and A.C.); F.R.S.-FNRS-Te´ le´ vie grants 7.8504.20, 7.4502.21, and 7.8508.22 (M. Szpakowska and A.C.); St. Jude GPCR Research Collaborative (to M.M.B.); AstraZeneca Blue Sky Fund grant BSF17 (to M.M.B. and G.S.); Swiss National Science Foundation grant P2ELP3_18910 (to D.M.); CPRIT Scholar in Cancer Research grant RR160021 (to N.S.); Alfred P. Sloan Scholar Research Fellowship grant FG- 2018-10723 (to N.S.); Blanton-Davis Ovarian Cancer Research Program (to N.S.); Andrew Sabin Family Foundation Fellowship (to N.S.); Ovarian Cancer Research Alliance Early Career Award grant 649968 (to N.S.). Publisher Copyright: © 2025 The Authors

PY - 2025/6/26

Y1 - 2025/6/26

N2 - 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.

AB - 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.

KW - chemokine

KW - chemotaxis

KW - data science

KW - GPCR

KW - machine learning

KW - polymorphism

KW - protein-protein interaction

KW - selectivity determinants

KW - short linear motif

KW - unstructured protein

KW - Amino Acid Sequence

KW - Humans

KW - Models, Molecular

KW - Chemokines/metabolism

KW - Receptors, Chemokine/metabolism

KW - Receptors, G-Protein-Coupled/metabolism

KW - Protein Binding

KW - Ligands

UR - https://www.scopus.com/pages/publications/105003480354

UR - https://pubmed.ncbi.nlm.nih.gov/40273912/

U2 - 10.1016/j.cell.2025.03.046

DO - 10.1016/j.cell.2025.03.046

M3 - Article

C2 - 40273912

AN - SCOPUS:105003480354

SN - 0092-8674

VL - 188

SP - 3603-3622.e27

JO - Cell

JF - Cell

IS - 13

ER -

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

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Keywords

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