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

Author

Listed:
  • Jan Bláha

    (Charles University
    EMBL, Hamburg Unit c/o DESY)

  • Tereza Skálová

    (BIOCEV Centre)

  • Barbora Kalousková

    (Charles University
    Institute of Applied Physics – Biophysics group, TU Wien)

  • Ondřej Skořepa

    (Charles University)

  • Denis Cmunt

    (Charles University
    University of Lausanne)

  • Valéria Grobárová

    (Charles University)

  • Samuel Pazicky

    (Charles University
    Nanyang Technological 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)

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.

Suggested Citation

  • Jan Bláha & Tereza Skálová & Barbora Kalousková & Ondřej Skořepa & Denis Cmunt & Valéria Grobárová & Samuel Pazicky & Edita Poláchová & Celeste Abreu & Jan Stránský & Tomáš Kovaľ & Jarmila Dušková & Y, 2022. "Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32577-6
    DOI: 10.1038/s41467-022-32577-6
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    References listed on IDEAS

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    1. Jean-Claude D. Schwartz & Xuewu Zhang & Alexander A. Fedorov & Stanley G. Nathenson & Steven C. Almo, 2001. "Structural basis for co-stimulation by the human CTLA-4/B7-2 complex," Nature, Nature, vol. 410(6828), pages 604-608, March.
    2. Gautham R. Balaji & Oscar A. Aguilar & Miho Tanaka & Miguel A. Shingu-Vazquez & Zhihui Fu & Benjamin S. Gully & Lewis L. Lanier & James R. Carlyle & Jamie Rossjohn & Richard Berry, 2018. "Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    3. Carin C. Stamper & Yan Zhang & James F. Tobin & David V. Erbe & Shinji Ikemizu & Simon J. Davis & Mark L. Stahl & Jasbir Seehra & William S. Somers & Lidia Mosyak, 2001. "Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses," Nature, Nature, vol. 410(6828), pages 608-611, March.
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    Cited by:

    1. Chuanyuan Wei & Wei Sun & Kangjie Shen & Jingqin Zhong & Wanlin Liu & Zixu Gao & Yu Xu & Lu Wang & Tu Hu & Ming Ren & Yinlam Li & Yu Zhu & Shaoluan Zheng & Ming Zhu & Rongkui Luo & Yanwen Yang & Yingy, 2023. "Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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