Distinct atypical chemokine receptor 1 determinants underlie bacterial toxins recognition and pore formation

Abstract

Atypical chemokine receptor 1 (ACKR1) is one of the most promiscuous receptors in the human chemokine system, engaging structurally diverse chemokines through a conformationally flexible N-terminal tail. This same interface is exploited by pathogens, including Plasmodium vivax and Staphylococcus aureus (SA), via a compact sulfotyrosine code. Among pathogenic proteins recognizing ACKR1, the SA leukocidin pair HlgAB is a notable exception. HlgAB-mediated pore formation is only weakly competed by chemokines, the Duffy binding protein, or antibodies targeting the receptor's N-terminus, leaving open how HlgAB engage ACKR1. Combining structural biology approaches with cell-based assays, we show that HlgA and HlgB engage ACKR1 sulfated N-terminus with distinct affinities and site hierarchies, with a single higher-affinity site for sulfated tyrosine 41 present in HlgA but absent in HlgB. Unexpectedly, this N-terminal engagement is dispensable for pore formation; productive lysis instead requires a separate interaction between the toxins and ACKR1 extracellular vestibule. These results define a two-step recognition mechanism, toxin capture by the sulfotyrosine N-terminus followed by vestibule-dependent pore formation, and extend the view that ACKR1 promiscuity arises from distributed, ligand-specific use of multiple receptor surfaces rather than a single adaptable interface.

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BibTeX RIS

BibTeX

@misc{fouillen2026distinct,
  title = {{Distinct atypical chemokine receptor 1 determinants underlie bacterial toxins recognition and pore formation}},
  author = {A. Fouillen and E. Logerot and Z. Ammar and T. Girbau and I. Brabet and O. Otun and R. Ben Boubaker and C. Le Drezen and M. Bacia-Verloop and A. Desfosses and C. Leyrat and S. Granier and C. Bechara},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.07.749789},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749789v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Distinct atypical chemokine receptor 1 determinants underlie bacterial toxins recognition and pore formation
AU  - A. Fouillen
AU  - E. Logerot
AU  - Z. Ammar
AU  - T. Girbau
AU  - I. Brabet
AU  - O. Otun
AU  - R. Ben Boubaker
AU  - C. Le Drezen
AU  - M. Bacia-Verloop
AU  - A. Desfosses
AU  - C. Leyrat
AU  - S. Granier
AU  - C. Bechara
PY  - 2026
DA  - 2026/09/07
PB  - bioRxiv
DO  - 10.64898/2026.09.07.749789
UR  - https://www.biorxiv.org/content/10.64898/2026.09.07.749789v1
AB  - Atypical chemokine receptor 1 (ACKR1) is one of the most promiscuous receptors in the human chemokine system, engaging structurally diverse chemokines through a conformationally flexible N-terminal tail. This same interface is exploited by pathogens, including Plasmodium vivax and Staphylococcus aureus (SA), via a compact sulfotyrosine code. Among pathogenic proteins recognizing ACKR1, the SA leukocidin pair HlgAB is a notable exception. HlgAB-mediated pore formation is only weakly competed by chemokines, the Duffy binding protein, or antibodies targeting the receptor's N-terminus, leaving open how HlgAB engage ACKR1. Combining structural biology approaches with cell-based assays, we show that HlgA and HlgB engage ACKR1 sulfated N-terminus with distinct affinities and site hierarchies, with a single higher-affinity site for sulfated tyrosine 41 present in HlgA but absent in HlgB. Unexpectedly, this N-terminal engagement is dispensable for pore formation; productive lysis instead requires a separate interaction between the toxins and ACKR1 extracellular vestibule. These results define a two-step recognition mechanism, toxin capture by the sulfotyrosine N-terminus followed by vestibule-dependent pore formation, and extend the view that ACKR1 promiscuity arises from distributed, ligand-specific use of multiple receptor surfaces rather than a single adaptable interface.
ER  -

Abstract

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