Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT)
| Autor: | Felix A. Deuss, Jamie Rossjohn, Benjamin S. Gully, Richard Berry |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
T cell Nectins Immunoglobulin domain Biology Crystallography X-Ray Biochemistry Protein Structure Secondary Natural killer cell 03 medical and health sciences Protein Domains TIGIT Nectin medicine Humans Receptors Immunologic Protein Structure Quaternary Receptor Molecular Biology Genetics Cell adhesion molecule Cell Biology Ligand (biochemistry) 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Mutagenesis Protein Structure and Folding Cell Adhesion Molecules |
| Zdroj: | Journal of Biological Chemistry. 292:11413-11422 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m117.786483 |
| Popis: | T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. Although the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μm, which was moderately lower than the affinity observed for the TIGIT/necl-5 interaction (3.2 μm). The TIGIT/nectin-2 binding disrupted pre-assembled nectin-2 oligomers, suggesting that receptor-ligand and ligand-ligand associations are mutually exclusive events. Indeed, the crystal structure of TIGIT bound to the first immunoglobulin domain of nectin-2 indicated that the receptor and ligand dock using the same molecular surface and a conserved “lock and key” binding motifs previously observed to mediate nectin/nectin homotypic interactions as well as TIGIT/necl-5 recognition. Using a mutagenesis approach, we dissected the energetic basis for the TIGIT/nectin-2 interaction and revealed that an “aromatic key” of nectin-2 is critical for this interaction, whereas variations in the lock were tolerated. Moreover, we found that the C-C′ loop of the ligand dictates the TIGIT binding hierarchy. Altogether, these findings broaden our understanding of nectin/nectin receptor interactions and have implications for better understanding the molecular basis for autoimmune disease and cancer. |
| Databáze: | OpenAIRE |
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