Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse

Jan Bláha, Tereza Skálová, Barbora Kalousková, Ondřej Skořepa, Denis Cmunt, Valéria Grobárová, Samuel Pazicky, Edita Poláchová, Celeste Abreu, Jan Stránský, Tomáš Kovaľ, Jarmila Dušková, Yuguang Zhao, Karl Harlos, Jindřich Hašek, Jan Dohnálek and Ondřej Vaněk ()
Additional contact information
Jan Bláha: Charles University
Tereza Skálová: BIOCEV Centre
Barbora Kalousková: Charles University
Ondřej Skořepa: Charles University
Denis Cmunt: Charles University
Valéria Grobárová: Charles University
Samuel Pazicky: Charles University
Edita Poláchová: Charles University
Celeste Abreu: Charles University
Jan Stránský: BIOCEV Centre
Tomáš Kovaľ: BIOCEV Centre
Jarmila Dušková: BIOCEV Centre
Yuguang Zhao: University of Oxford
Karl Harlos: University of Oxford
Jindřich Hašek: BIOCEV Centre
Jan Dohnálek: BIOCEV Centre
Ondřej Vaněk: Charles University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Signaling by the human C-type lectin-like receptor, natural killer (NK) cell inhibitory receptor NKR-P1, has a critical role in many immune-related diseases and cancer. C-type lectin-like receptors have weak affinities to their ligands; therefore, setting up a comprehensive model of NKR-P1-LLT1 interactions that considers the natural state of the receptor on the cell surface is necessary to understand its functions. Here we report the crystal structures of the NKR-P1 and NKR-P1:LLT1 complexes, which provides evidence that NKR-P1 forms homodimers in an unexpected arrangement to enable LLT1 binding in two modes, bridging two LLT1 molecules. These interaction clusters are suggestive of an inhibitory immune synapse. By observing the formation of these clusters in solution using SEC-SAXS analysis, by dSTORM super-resolution microscopy on the cell surface, and by following their role in receptor signaling with freshly isolated NK cells, we show that only the ligation of both LLT1 binding interfaces leads to effective NKR-P1 inhibitory signaling. In summary, our findings collectively support a model of NKR-P1:LLT1 clustering, which allows the interacting proteins to overcome weak ligand-receptor affinity and to trigger signal transduction upon cellular contact in the immune synapse.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32577-6

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DOI: 10.1038/s41467-022-32577-6

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