Abstract
The interaction between natural killer (NK) cell inhibitory receptors and their cognate ligands constitutes a key mechanism by which healthy tissues are protected from NK cell-mediated lysis. However, self-ligand recognition remains poorly understood within the prototypical NKR-P1 receptor family. Here we report the structure of the inhibitory NKR-P1B receptor bound to its cognate host ligand, Clr-b. NKR-P1B and Clr-b interact via a head-to-head docking mode through an interface that includes a large array of polar interactions. NKR-P1B:Clr-b recognition is extremely sensitive to mutations at the heterodimeric interface, with most mutations severely impacting both Clr-b binding and NKR-P1B receptor function to implicate a low affinity interaction. Within the structure, two NKR-P1B:Clr-b complexes are cross-linked by a non-classic NKR-P1B homodimer, and the disruption of homodimer formation abrogates Clr-b recognition. These data provide an insight into a fundamental missing-self recognition system and suggest an avidity-based mechanism underpins NKR-P1B receptor function.
Highlights
The interaction between natural killer (NK) cell inhibitory receptors and their cognate ligands constitutes a key mechanism by which healthy tissues are protected from NK cell-mediated lysis
Alternate MHC-I-independent missing-self recognition systems have emerged as important regulators of NK cell function
Our structural analysis revealed that Clr-b formed a homodimer that was classic of CTLDcontaining proteins, while NK cell receptors (NKR)-P1B did not
Summary
The interaction between natural killer (NK) cell inhibitory receptors and their cognate ligands constitutes a key mechanism by which healthy tissues are protected from NK cell-mediated lysis. Two NKR-P1B:Clr-b complexes are cross-linked by a non-classic NKR-P1B homodimer, and the disruption of homodimer formation abrogates Clr-b recognition These data provide an insight into a fundamental missing-self recognition system and suggest an avidity-based mechanism underpins NKR-P1B receptor function. The NKC is located on chromosome 6 and includes the Ly49, the CD94/NKG2, and the NKR-P1 receptors[4] Each of these receptor families are architecturally similar, being type II transmembrane proteins that possess C-type lectin-like domains (CTLD). While the Clr ligands form homodimers whose architecture is conserved among other CTLD-containing proteins ( termed classic homodimers), the mode of NKR-P1 receptor self-association is less clear Within this axis, the most studied interaction is that of NKR-P1B with Clr-b. This study provides broad insight into the mechanisms of MHC-I-independent missing-self recognition and NKRP1B receptor function
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