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@article{2262422,
author = {Blaha, Jan and Skalova, Tereza and Kalouskova, Barbora and Skorepa, Ondrej and Cmunt, Denis and Grobarova, Valeria and Pazicky, Samuel and Polachova, Edita and Abreu, Celeste and Stransky, Jan and Koval, Tomas and Duskova, Jarmila and Zhao, Yuguang and Harlos, Karl and Hasek, Jindrich and Dohnalek, Jan and Vanek, Ondrej},
article_location = {London},
article_number = {1},
doi = {http://dx.doi.org/10.1038/s41467-022-32577-6},
keywords = {CD161 antigen; dectin 1; protein; protein llt1; unclassified drug},
language = {eng},
issn = {2041-1723},
journal = {Nature Communications},
title = {Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse},
url = {https://www.nature.com/articles/s41467-022-32577-6},
volume = {13},
year = {2022}
}
TY - JOUR
ID - 2262422
AU - Blaha, Jan - Skalova, Tereza - Kalouskova, Barbora - Skorepa, Ondrej - Cmunt, Denis - Grobarova, Valeria - Pazicky, Samuel - Polachova, Edita - Abreu, Celeste - Stransky, Jan - Koval, Tomas - Duskova, Jarmila - Zhao, Yuguang - Harlos, Karl - Hasek, Jindrich - Dohnalek, Jan - Vanek, Ondrej
PY - 2022
TI - Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse
JF - Nature Communications
VL - 13
IS - 1
SP - 5022
EP - 5022
PB - Nature Publishing Group
SN - 20411723
KW - CD161 antigen
KW - dectin 1
KW - protein
KW - protein llt1
KW - unclassified drug
UR - https://www.nature.com/articles/s41467-022-32577-6
N2 - NKR-P1 is an inhibitory receptor on the surface of natural killer cells, and its engagement with the ligand LLT1 on activated monocytes and B cells triggers NK cell self-tolerance and other immunological processes. Here authors set up a comprehensive, structure-based model of NKR-P1-LLT1 interaction that involves NKR-P1 homodimer formation and subsequent bridging of two LLT1 molecules. 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.
ER -
BLAHA, Jan, Tereza SKALOVA, Barbora KALOUSKOVA, Ondrej SKOREPA, Denis CMUNT, Valeria GROBAROVA, Samuel PAZICKY, Edita POLACHOVA, Celeste ABREU, Jan STRANSKY, Tomas KOVAL, Jarmila DUSKOVA, Yuguang ZHAO, Karl HARLOS, Jindrich HASEK, Jan DOHNALEK and Ondrej VANEK. Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse. \textit{Nature Communications}. London: Nature Publishing Group, 2022, vol.~13, No~1, p.~5022-5039. ISSN~2041-1723. Available from: https://dx.doi.org/10.1038/s41467-022-32577-6.
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