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

Distinct atypical chemokine receptor 1 (ACKR1) determinants underlie bacterial toxins recognition and pore formation. Atypical chemokine receptor 1 (ACKR1) is a promiscuous receptor that interacts with various chemokines through a flexible N-terminal tail. Pathogens such as Plasmodium vivax and Staphylococcus aureus (SA) exploit this interface using a sulfotyrosine code.

Among SA's toxic proteins, HlgAB-mediated pore formation is only weakly competed by chemokines, the Duffy binding protein, or antibodies targeting ACKR1's N-terminus. Using structural biology and cell-based assays, researchers demonstrated that HlgA and HlgB bind to ACKR1's sulfated N-terminus with varying affinities and site hierarchies.

HlgA has a single higher-affinity site for sulfated tyrosine 41, absent in HlgB. Surprisingly, this N-terminal engagement is not essential for pore formation; instead, productive lysis relies on an independent interaction between the toxins and ACKR1's extracellular vestibule. These findings reveal a two-step recognition mechanism, where the toxins first bind to the sulfotyrosine N-terminus and then are guided to the vestibule for pore formation, highlighting ACKR1's promiscuity from distributed, ligand-specific receptor surfaces.